Biochemical analysis and therapy of thiamine-responsive lactic acidemia

据报道，许多乳酸血症患者在服用硫胺素后临床症状有所改善。在大多数情况下，这些改善背后的生化机制尚不清楚。在这项研究中，丙酮酸脱氢酶复合体(PDHC)在硫胺素反应性乳酸酸血症的病因学中的作用进行了研究。测定了PDHC活性与TPP浓度的关系。从13例对硫胺素治疗有反应的乳酸血症患者获得培养的淋巴母细胞、培养的皮肤成纤维细胞和肌肉活检组织，并检测PDHC对刺激丙酮酸代谢的二氯乙酸钠的反应。根据PDHC活性测定，这13例硫胺素反应性乳酸血症患者可分为三组。组1包括2例PDHC活性非常低的患者，经DCA治疗后未见升高，但随TP浓度的增加而升高。组2包括5例患者，其PDHC活性在低浓度TPP时低于正常，经DCA治疗后升高，而在高浓度时正常。第1组和第2组的PDHC缺陷是由于PDHC对TP的亲和力降低所致。第3组包括6例PDHC活性在低浓度和高浓度TPP下均正常的患者，经DCA治疗后PDHC活性增加。这些数据表明，一些硫胺素反应性乳酸酸血症患者可能患有PDHC，这需要TPP水平的升高才能达到最大活性。对于这种类型的PDHC缺乏症的诊断，应在低浓度(1×10；-4；mM)的TPP下测定PDHC活性。

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.