Thiamine-responsive congenital lactic acidosis: clinical and biochemical studies.
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 alpha-ketoglutarate, alpha-ketoadipate, and branched chain ketoacids, indicating functional impairment of thiamine-requiring enzymes, such as pyruvate dehydrogenase complex, alpha-ketoglutarate dehydrogenase complex, alpha-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 alpha-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.
Toyoshima
Mitsuo
M
Division of Child Neurology, Institute of Neurological Science, Faculty of Medicine, Tottori University, Yonago, Japan.
Oka
Akira
A
Egi
Yoshiko
Y
Yamamoto
Toshiyuki
T
Onozuka
Mari
M
Nosaka
Kazuto
K
Naito
Etsuo
E
Yamada
Kazuo
K
D000140:Acidosis, Lactic / Q000151:congenital / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D013836:Thiamin Pyrophosphokinase / Q000235:genetics / Q000378:metabolism; D013831:Thiamine / Q000008:administration & dosage* / Q000493:pharmacokinetics
D026901:Membrane Transport Proteins; C120043:SLC19A2 protein, human; C492291:SLC19A3 protein, human; D007655:Ketoglutarate Dehydrogenase Complex; D013836:Thiamin Pyrophosphokinase; D013831:Thiamine