Thiamine-Responsive Congenital Lactic Acidosis: Clinical and Biochemical Studies - 20/08/11

Doi : 10.1016/j.pediatrneurol.2005.02.007

Mitsuo Toyoshima, MD ^⁎, Akira Oka, MD ^†, Yoshiko Egi, PhD ^‡, Toshiyuki Yamamoto, MD ^§, Mari Onozuka, PhD , Kazuto Nosaka, PhD ^¶, Etsuo Naito, MD ^#, Kazuo Yamada, MD
Division of Child Neurology, Institute of Neurological Science, Faculty of Medicine, Tottori University, Yonago
^† Division of Neurology, National Children’s Medical Center, Tokyo
^‡ Department of Nutrition, Suzugamine Women’s College, Hiroshima
^§ Division of Medical Genetics, Kanagawa Children’s Medical Center, Yokohama
Department of Biochemistry, Kyoto Prefectural University of Medicine, Kyoto
^¶ Department of Chemistry, Kyoto Prefectural University of Medicine, Kyoto
^# Department of Pediatrics, School of Medicine, University of Tokushima, Tokushima
Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Science, Faculty of Medicine, Tottori University, Yonago, Japan

Communications should be addressed to: Dr. Toyoshima; Department of Pediatrics; Tottori Prefectural Central Hospital; 730 Ezu; Tottori 680-0901 Japan

Résumé

We studied six infants with thiamine-responsive congenital lactic acidosis and normal pyruvate dehydrogenase complex activity in vitro, through clinical and biochemical analysis. In addition to elevated lactate and pyruvate levels, the data revealed increased urinary excretion of ⍺-ketoglutarate, ⍺-ketoadipate, and branched chain ketoacids, indicating functional impairment of thiamine-requiring enzymes, such as pyruvate dehydrogenase complex, ⍺-ketoglutarate dehydrogenase complex, ⍺-ketoadipate dehydrogenase, and branched chain amino acid dehydrogenase. The metabolism of thiamine has not been investigated in patients with thiamine-responsive congenital lactic acidosis. We evaluated two specific transport systems, THTR-1 (SLC19A2) and THTR-2 (SLC19A3), and a pyrophosphorylating enzyme of thiamine, thiamine pyrophosphokinase (hTPK 1), in addition to pyruvate dehydrogenase complex and ⍺-ketoglutarate dehydrogenase complex activity; no abnormality was found. Although the clinical features of thiamine-responsive congenital lactic acidosis are heterogeneous and clinical responses to thiamine administration vary, we emphasize the importance of early diagnosis and initiation of thiamine therapy before the occurrence of permanent brain damage. Careful monitoring of lactate and pyruvate would be useful in determining thiamine dosage.

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