title: Thiamine pyrophosphokinase deficiency in encephalopathic children with defects in the pyruvate oxidation pathway.
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.
authors.affiliation: Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria. h.mayr@salk.at
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
authors.forename: Peter
authors.initials: P
authors.lastname: Freisinger
authors.forename: Kurt
authors.initials: K
authors.lastname: Schlachter
authors.forename: Boris
authors.initials: B
authors.lastname: Rolinski
authors.forename: Franz A
authors.initials: FA
authors.lastname: Zimmermann
authors.forename: Thomas
authors.initials: T
authors.lastname: Scheffner
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.forename: Johannes
authors.initials: J
authors.lastname: Koch
authors.forename: Uwe
authors.initials: U
authors.lastname: Ahting
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
mesh_terms: D000015:Abnormalities, Multiple / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D000140:Acidosis, Lactic / Q000201:enzymology / Q000235:genetics; D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D001928:Brain Diseases, Metabolic / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D002648:Child; D004252:DNA Mutational Analysis; D057075:Enzyme Assays; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D009154:Mutation; D010084:Oxidation-Reduction; D010375:Pedigree; D019289:Pyruvic Acid / Q000378:metabolism*; D013836:Thiamin Pyrophosphokinase / Q000172:deficiency* / Q000235:genetics; D013831:Thiamine / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D019289:Pyruvic Acid; D013836:Thiamin Pyrophosphokinase; D013831:Thiamine