1. Thiamine pyrophosphokinase deficiency in encephalopathic children with defects in the pyruvate oxidation pathway.
- Author
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Mayr JA, Freisinger P, Schlachter K, Rolinski B, Zimmermann FA, Scheffner T, Haack TB, Koch J, Ahting U, Prokisch H, and Sperl W
- Subjects
- Abnormalities, Multiple drug therapy, Abnormalities, Multiple genetics, Acidosis, Lactic enzymology, Acidosis, Lactic genetics, Adolescent, Amino Acid Sequence, Base Sequence, Brain Diseases, Metabolic drug therapy, Brain Diseases, Metabolic genetics, Child, DNA Mutational Analysis, Enzyme Assays, Fatal Outcome, Female, Humans, Male, Molecular Sequence Data, Muscle, Skeletal enzymology, Muscle, Skeletal metabolism, Mutation, Oxidation-Reduction, Pedigree, Thiamin Pyrophosphokinase genetics, Thiamine blood, Thiamine metabolism, Thiamine therapeutic use, Abnormalities, Multiple enzymology, Brain Diseases, Metabolic enzymology, Metabolic Networks and Pathways genetics, Pyruvic Acid metabolism, Thiamin Pyrophosphokinase deficiency
- Abstract
Thiamine pyrophosphate (TPP) is an essential cofactor of the cytosolic transketolase and of three mitochondrial enzymes involved in the oxidative decarboxylation of either pyruvate, α-ketoglutarate or branched chain amino acids. Thiamine is taken up by specific transporters into the cell and converted to the active TPP by thiamine pyrophosphokinase (TPK) in the cytosol from where it can be transported into mitochondria. Here, we report five individuals from three families presenting with variable degrees of ataxia, psychomotor retardation, progressive dystonia, and lactic acidosis. Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate but normal pyruvate dehydrogenase complex activity in the presence of excess TPP. A reduced concentration of TPP was found in the muscle and blood. Mutation analysis of TPK1 uncovered three missense, one splice-site, and one frameshift mutation resulting in decreased TPK protein levels., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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