Biochemical analysis and therapy of thiamine-responsive lactic acidemia

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Many patients with lactic acidemia have been reported to show clinical improvement in response to the administration of thiamine. In most cases, the biochemical mechanism underlying these improvements is unknown.In this study, the role of the pyruvate dehydrogenase complex (PDHC) in the etiology of thiamine-responsive lactic acidemia was examined. The relationship of the activity of PDHC to thiamine pyrophosphate (TPP) concentration was determined. The response of PDHC to treatment with sodium dichloroacetate (DCA) that stimulates pyruvate metabolism was also examined.Cultured lymphoblastoid cells, cultured skin fibroblasts, and biopsied muscle were obtained from 13 patients with lactic acidemia that was responsive to thiamine therapy. These 13 patients with thiamine-responsive lactic acidemia could be devided into three groups based on measurment of PDHC activity. Group 1 included two patients whose PDHC activity was very low, was not increased by treatment with DCA,and was increased by increased concentration of TPP.Group 2 included five patients whose PDHC activity was below normal at low concentration of TPP,was increased by treatment with DCA,and was normal at high concentration of TPP.Therefore, PDHC deficiency in the patients in groups 1 and 2 was due to a decreased affinity of PDHC for TPP.Group 3 included six patients whose PDHC activity was normal at both low and high concentration of TPP and was increased by treatment with DCA.These data indicated that some patients with thiamine-responsive lactic acidemia may have PDHC which requires elevated levels of TPP for maximal activity. For diagnose of this type of PDHC deficiency, PDHC activity should be determined at low concentration (1x10^<-4>mM) of TPP.