title: Thiamine-responsive pyruvate dehydrogenase deficiency in two patients caused by a point mutation (F205L and L216F) within the thiamine pyrophosphate binding region.
abstract: The human pyruvate dehydrogenase complex (PDHC) catalyzes the thiamine-dependent decarboxylation of pyruvate. Thiamine treatment is very effective for some patients with PDHC deficiency. Among these patients, five mutations of the pyruvate dehydrogenase (E1)alpha subunit have been reported previously: H44R, R88S, G89S, R263G, and V389fs. All five mutations are in a region outside the thiamine pyrophosphate (TPP)-binding region of the E1alpha subunit. We report the biochemical and molecular analysis of two patients with clinically thiamine-responsive lactic acidemia. The PDHC activity was assayed using two different concentrations of TPP. These two patients displayed very low PDHC activity in the presence of a low (1 x 10(-4) mM) TPP concentration, but their PDHC activity significantly increased at a high (0.4 mM) TPP concentration. Therefore, the PDHC deficiency in these two patients was due to a decreased affinity of PDHC for TPP. Treatment of both patients with thiamine resulted in a reduction in the serum lactate concentration and clinical improvement, suggesting that these two patients have a thiamine-responsive PDHC deficiency. The DNA sequence of these two male patients' X-linked E1alpha subunit revealed a point mutation (F205L and L216F) within the TPP-binding region in exon 7.
authors.affiliation: Department of Pediatrics, School of Medicine, University of Tokushima, Kuramoto Cho 3, Tokushima, Japan. enaito@clin.med.tokushima-u.ac.jp
authors.forename: Etsuo
authors.initials: E
authors.lastname: Naito
authors.forename: Michinori
authors.initials: M
authors.lastname: Ito
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yokota
authors.forename: Takahiko
authors.initials: T
authors.lastname: Saijo
authors.forename: Junko
authors.initials: J
authors.lastname: Matsuda
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Seiko
authors.initials: S
authors.lastname: Kitamura
authors.forename: Eiko
authors.initials: E
authors.lastname: Takada
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Horii
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kuroda
mesh_terms: D001665:Binding Sites; D002478:Cells, Cultured; D002648:Child; D005091:Exons; D006801:Humans; D007223:Infant; D019344:Lactic Acid / Q000097:blood; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology; D008297:Male; D017354:Point Mutation; D011767:Pyruvate Decarboxylase / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D013831:Thiamine / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D019344:Lactic Acid; D011767:Pyruvate Decarboxylase; D013831:Thiamine