European Journal of Pediatrics

, Volume 154, Issue 11, pp 928–932

Therapy of complex I deficiency: Peripheral neuropathy during dichloroacetate therapy

  • G. Kurlemann
  • I. Paetzke
  • H. Möller
  • H. Masur
  • G. Schuierer
  • J. Weglage
  • H. G. Koch
Neuropediatrics Original Paper

Abstract

A therapeutic trial with polyvitamins and dichloroacetate (DCA) in combination with thiamine in a 13-year-old girl with complex I deficiency is reported. The polyvitamin therapy included thiamine, riboflavin, ascorbate, coenzyme Q 10 and carnitine. This therapeutic regine was used over a period of 17 months without any effect. Although DCA lowered the lactate concentration in blood and CNS — measured by magnetic resonance spectroscopy — no clinical benefit was achieved. After 20 weeks of DCA therapy a distal polyneuropathy with areflexia developed although 100 mg thiamine daily as comedication was given from the beginning of DCA therapy. Nerve conduction velocity of the peroneal nerve was not detectable, sensible evoked potentials of the tibialis posterious nerve were normal. This side-effect resolved completely within 6 months after omission of DCA. Our observation suggests a direct toxic effect of DCA only on the peripheral nervous system in our patient since several cerebral MRI and magnetic resonance spectroscopy studies showed no abnormalities.

Conclusion

DCA lowers the lactate concentration in children with complex I deficiency of the respiratory chain in a dose of 100 mg/kg body weight without clinical benefit. Reversible peripheral polyneuropathy may develop under DCA therapy despite thiamine medication.

Key words

Complex I deficiency Polyvitamin therapy Dichloroacetate therapy Polyneuropathy Thiamine administration 

Abbreviations

DCA

dichloroacetate

MRS

magnetic resonance spectroscopy

MELAS

mitochondrial encephalopathy, lactate acidosis, stroke like episodes

MERRF

mitochondrial encephalopathy with ragged red fibres

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Arts WFM, Scholte HR, Bogaard JM, Kerrebijn KF, Luyt-Houwen JEM (1983) NADH-CoQ reductase deficient myopathy: successful treatment with riboflavin. Lancet II: 581–582CrossRefGoogle Scholar
  2. 2.
    Bernsen PLJ, Gabreels FJM, Ruitenbeck W, Sengers RCA, Stadhouders AM, Renier WO (1991) Successful treatment of pure myopathy, associated with complex I deficiency, with riboflavin and carnitin. Arch Neurol 48: 334–338PubMedGoogle Scholar
  3. 3.
    Bottomley PA (1987) Spatial localisation in NMR spectroscopy in vivo. Ann NY Acad Sci 508: 333–348PubMedGoogle Scholar
  4. 4.
    Clark JB, Hayes DJ, Morgan-Highes JA, Byrne E (1984) Mitochondrial myopathies: disorders of the respiratory chain and oxidative phosphorylation. J Inherited Metab Dis 7 [Suppl 1]: 62–68CrossRefGoogle Scholar
  5. 5.
    Evans OB (1985) Lactic acidosis in childhood: part I. Pediatr Neurol 1: 325–328CrossRefPubMedGoogle Scholar
  6. 6.
    Fischer JC (1985) Mitochondrial myopathies and respiratory chain defects. Dissertation, University of NijmegenGoogle Scholar
  7. 7.
    Hammans SR, Morgan-Hughes JA (1994) Mitochondrial myopathies: clinical features, investigation, treatment and genetic counselling. In: Schapira AHV, DiMauro S (ed) Mitochondrial disorders in neurology. Butterworth-Heinemann, Oxford, pp 49–74Google Scholar
  8. 8.
    Ichiki T, Tanaka M, Nishikimi M, Suzuki H, Takayuki O, Kobayashi M, Wada Y (1988) Deficiency of subunits of complex I and mitochondrial encephalomyopathy. Ann Neurol 23: 287–294CrossRefPubMedGoogle Scholar
  9. 9.
    Kudoroda Y, Ito M, Takeda E, Naito E, Hwang TJ, Hashimoto T, Miyado M, Masuda M, Yamashita K, Adachi T, Suzuki Y, Nishiyama K (1986) Treatment of chronic congenital lactic acidosis by oral administration of dichloracetate. J Inherited Metab Dis 9: 244–252CrossRefPubMedGoogle Scholar
  10. 10.
    Kuroda Y, Natio E, Takeda E, Yokato I, Miyao M (1987) Congenital lactic acidosis. Enzyme 38: 108–114PubMedGoogle Scholar
  11. 11.
    Koga Y, Nonaka I, Kobayashi M, Tojyo M, Nihei K (1988) Findings in muscle in complex I (NADH coenzyme Q reductase) deficiency. Ann Neurol 24: 749–756CrossRefPubMedGoogle Scholar
  12. 12.
    Lilienthal JL, Zierler KL, Folk BP (1950) A reference base and system for analysis of muscle constituents. J Biol Chem 182: 501–508Google Scholar
  13. 13.
    McKhann C, Francois B, Evrard P (1980) Longterm use of lower doses of dichloracetate in a child with congenital lactic acidoses. Pediatr Res 14: 167Google Scholar
  14. 14.
    Moore GW, Swift LL, Rabinowitz D, Croford OB, Oates JA, Stacpole PW (1979) Reduction of serum cholesterol in two patients with homozygous familial hypercholesterolemia by dichloroacetate. Atherosclerosis 33: 285–293PubMedGoogle Scholar
  15. 15.
    Morgan-Hughes JA, Hayes DJ, Cooper M, Clark JB (1985) Mitochondrial myopathies: deficiences localized to complex I and complex III of the mitochondrial respiratory chain. Bio Soc Trans 13: 648–650Google Scholar
  16. 16.
    Petty RKH, Harding AE, Morgan-Hughes JA (1986) The clinical features of mitochondrial myopathy. Brain 109: 915–938PubMedGoogle Scholar
  17. 17.
    Przyrembel H (1987) Therapy of mitochondrial disorders. J Inherited Metab Dis 10: 129–146CrossRefPubMedGoogle Scholar
  18. 18.
    Roodhooft AM, Acker KJ, Martin JJ, Ceuterick C, Scholte HR, Luyt-Houwen IEM (1986) Benign mitochondrial myopathy with deficiency of NADH-CoQ reductase and cytochrome c oxidase. Neuropediatrics 17: 221–226PubMedGoogle Scholar
  19. 19.
    Schon EA (1994) Mitochondrial DNA and the genetics of mitochondrial disease. In: Schapira AHV, DiMauro S (ed) Mitochondrial disorders in neurology, Butterworth-Heinemann, Oxford, pp 31–48Google Scholar
  20. 20.
    Sottocasa GL, Kuylenstierna B, Ernester L (1967) An electrontransport system associated with the outer membrane of liver mitochondria. J Cell Biol 32: 415–438CrossRefPubMedGoogle Scholar
  21. 21.
    Stacpole PW (1989) The pharmacology of dichloracetate. Metabolism 38: 1124–1144CrossRefPubMedGoogle Scholar
  22. 22.
    Stitt M (1985) Citrate synthase. In: Bergmeyer HU (ed) Methods of enzymatic analysis, 3 rd edn. Vol IV, VCH-Verlagsgesellschaft GmbH, Weinheim, pp 353–358Google Scholar
  23. 23.
    Trijbels JMF, Sengers RCA, Ruitenbeck W, Fischer JC, Bakkeren JAJM, Janssen AJM (1988) Disorders of the mitochondrial respiratory chain: clinical manifestation and diagnostic approach. Eur J Pediatr 148: 92–97CrossRefPubMedGoogle Scholar
  24. 24.
    Williams SR (1992) In vivo proton spectroscopy. Experimental aspects and potential. In: Diehl P, Fluck E, Günther H, Kosfeld R, Seelig J (eds) NMR basic principles and progress. Vol 28. Springer Verlag, Berlin Heidelberg New York, pp 55–72Google Scholar
  25. 25.
    Wharton DC, Tzagoloff A (1967) Cytochrome oxidase from beef heart mitochondria. Methods Enzymol 10: 245–250Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • G. Kurlemann
    • 1
  • I. Paetzke
    • 2
  • H. Möller
    • 3
  • H. Masur
    • 1
  • G. Schuierer
    • 4
  • J. Weglage
    • 1
  • H. G. Koch
    • 1
  1. 1.Children's HospitalMünsterGermany
  2. 2.Institut für Klinische ChemieStadtisches KrankenhausMünchen-SchwabingGermany
  3. 3.Institut of Physical ChemistryUniversity of MünsterGermany
  4. 4.Institute of Clinical RadiologyUniversity of MünsterGermany

Personalised recommendations