Abstract
Dichloroacetate (DCA) is a structural analog of pyruvate that has been recommended for the treatment of primary lactic acidemia, particularly in patients with pyruvate dehydrogenase (PDHC) deficiency. Recent reports have demonstrated that the response to DCA may depend on the type of molecular abnormality. In this study, we investigated the response to DCA in various PDHC-deficient cell lines and tried to determine the mechanism involved. The effect of chronic 3-d DCA treatment on PDHC activity was assessed in two PDHC-deficient cell lines, each with a different point mutation in the E1α subunit gene (R378C and R88C), and one cell line in which an 8-bp tandem repeat was deleted (W383 del). Only two (R378C and R88C) of the three PDHC-deficient cell lines with very low levels of PDHC activity and unstable polypeptides were sensitive to chronic DCA treatment. In these cell lines, DCA treatment resulted in an increase in PDHC activity by 125 and 70%, respectively, with concomitant increases of 121 and 130% in steady-state levels of immunoreactive E1α. DCA treatment reduced the turnover of the E1α subunit in R378C and R88C mutant cells with no significant effect on the E1β subunit. Chronic DCA treatment significantly improved the metabolic function of PDHC in digitonin-permeabilized R378C and R88C fibroblasts. The occurrence of DCA-sensitive mutations suggests that DCA treatment is potentially useful as an adjuvant to ketogenic and vitamin treatment in PDHC-deficient patients.
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Abbreviations
- DCA:
-
dichloroacetic acid
- PDHC:
-
pyruvate dehydrogenase complex
- SSCP:
-
single-strand conformation polymorphism
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Acknowledgements
The authors thank Prof. J.M. Saudubray, J.M. Pedespan, and Dr. H. Ogier de Baulny from the Pediatric Department [Hôpital Enfants Malades (J.M.S.) and Hôpital Robert Debré (H.O.), Paris, and Hôpital Pellegrin Bordeaux (J.M.P.)] for providing us with the opportunity of working with their patients. We also thank Prof G. Lindsay for his kind gift of polyclonal antibodies against PDHC purified from pig heart. We thank Dr. B. Desbuquois and Dr. F. Authier for critical reading of this manuscript. We also thank Y. Deris for expert artwork.
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Supported by grants from Association Française Contre les Myopathies and by the European Commission, contract no. QL G2-CT-1999-00660.
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Fouque, F., Brivet, M., Boutron, A. et al. Differential Effect of DCA Treatment on the Pyruvate Dehydrogenase Complex in Patients with Severe PDHC Deficiency. Pediatr Res 53, 793–799 (2003). https://doi.org/10.1203/01.PDR.0000057987.46622.64
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DOI: https://doi.org/10.1203/01.PDR.0000057987.46622.64
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