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Valproate-induced hepatic failure in a case of cytochromec oxidase deficiency

Abstract

We report a 3 year-old girl with a myoclonic epilepsy. A fatal hepatic failure occurred after 3 months of valproate (VPA) therapy. In this patient, a defect of cytochromec oxidase (COX) was demonstrated in her circulating lymphocytes. The enzyme was also found to be deficient in post-mortem liver and in cultured skin fibroblasts. However, a fully functional respiratory chain was found in muscle. VPA administration apparently triggered the hepatic failure, given this patient's background of partial COX deficiency.

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Abbreviations

COX :

cytochromec oxidase

VPA :

valproate

References

  1. 1.

    Boustany RN, Aprille JR, Halperin J, Levy H, DeLong GR (1983) Mitochondrial cytochrome deficiency presenting as a myopathy with hypotonia, external ophtalmoplegia, and lactic acidosis in an infant and as fatal hepatopathy in a second cousin. Ann Neurol 14:462–470

  2. 2.

    Bremer HJ, Duran M, Kamerling JP, Przyrembel H, Wadman SK (1981) Disturbances of aminoacid metabolism: clinical chemistry and diagnosis. Urban and Schwarzenberg, Baltimore

  3. 3.

    Brown JK (1988) Valproate toxicity. Dev Med Child Neurol 30:121–125

  4. 4.

    Cormier V, Rustin P, Bonnefont JP, Rambaud C, Vassault A, Rabier D, Parvy P, Couderc S, Parrot-Roulaud F, Carré M, Risse JC, Cahuzac C, Saudubray JM, Rötig A, Hubert P, Munnich A (1991) Hepatic failure in disorders of oxidative phosphorylation with neonatal onset. J Pediatr 119: 951–954

  5. 5.

    Coulter DL (1991) Carnitine, valproate, and toxicity. J Child Neurol 6:7–14

  6. 6.

    Dreifuss FE, Langer DH, Moline KA, Maxwell JE (1989) Valproic acid hepatic fatalities. II. US experience since 1984. Neurology 39:201–207

  7. 7.

    Goodman SI, Markey SP (1981) Diagnosis of organic acidemias by gas chromatography-mass spectrometry. Laboratory and research methods in biology and medicine vol. 6. AR Liss, New York

  8. 8.

    Kondo T, Kaneko S, Otani K, Ishia M, Hirano T, Fukushima Y, Muranaka H, Koide N, Yokoyama M (1992) Associations between risk factors for valproate hepatotoxicity and altered valproate metabolism. Epilepsia 33: 172–177

  9. 9.

    Merle P, Kadenbach B (1980) On the heterogeneity of the vertebrate cytochromec oxydase polypeptide chain composition. Hoppe-Seylers Z Physiol Chem 361:1257–1259

  10. 10.

    Munnich A, Rustin P, Rötig A, Chretien D, Bonnefont JP, Nuttin C, Cormier V, Vassault A, Parvy P, Bardet J, Charpentier C, Rabier D, Saudubray JM (1992) Clinical aspects of mitochondrial disorders. J Inherited Metab Dis 15:448–455

  11. 11.

    Parrot-Roulaud F, Carre M, Lamirau T, Letellier T, Malgat M, Mazat JP, Munnich A, Demarquez JL (1991) Fatal neonatal hepatocellular deficiency with lactic acidosis: a defect of the respiratory chain. J Inherited Metab Dis 14:289–292

  12. 12.

    Rettie AE, Rettenmeir AW, Howald WN, Baillie TA (1987) Cytochrome P-450 catalysed formation of Δ4, a toxic metabolite of valproic acid. Science 235:890–893

  13. 13.

    Rötig A, Cormier V, Blanche S, Bonnefont JP, Ledeist F, Romero N, Schmitz J, Rustin P, Fischer A, Saudubray JM, Munnich A (1990) Pearson's marrow-pancreas syndrome: a multisystem mitochondrial disorder in infancy. Clin Invest 86:1601–1608

  14. 14.

    Rustin P, Chretien D, Bourgeron T, Wucher A, Saudubray JM, Rötig A, Munnich A (1991) Assessment of the mitochondrial respiratory chain. Lancet 338:60

  15. 15.

    Vassault A, Bonnefont JP, Specola N, Saudubray JM (1991) Lactate, pyruvate and ketone bodies. In: Homme FA (ed) Techniques in diagnostic human biochemical genetics. A laboratory manual. Wiley-Liss, New York, pp 285–308

  16. 16.

    Willmore LJ, Triggs WJ, Pellock JM (1991) Valproate toxicity: risk-screening strategies. J Child Neurol 6:3–6

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Correspondence to B. Chabrol.

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Chabrol, B., Mancini, J., Chretien, D. et al. Valproate-induced hepatic failure in a case of cytochromec oxidase deficiency. Eur J Pediatr 153, 133–135 (1994). https://doi.org/10.1007/BF01959226

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Key words

  • Hepatic failure
  • COX defect
  • Valproate
  • Child