title: Genetic defects in the hexosamine and sialic acid biosynthesis pathway.
abstract: BACKGROUND
  Congenital disorders of glycosylation are caused by defects in the glycosylation of proteins and lipids. Classically, gene defects with multisystem disease have been identified in the ubiquitously expressed glycosyltransferases required for protein N-glycosylation. An increasing number of defects are being described in sugar supply pathways for protein glycosylation with tissue-restricted clinical symptoms.
  
  
  METHODS
  In this review, we address the hexosamine and sialic acid biosynthesis pathways in sugar metabolism. GFPT1, PGM3 and GNE are essential for synthesis of nucleotide sugars uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) and cytidine-5'-monophospho-N-acetylneuraminic acid (CMP-sialic acid) as precursors for various glycosylation pathways. Defects in these enzymes result in contrasting clinical phenotypes of congenital myasthenia, immunodeficiency or adult-onset myopathy, respectively. We therefore discuss the biochemical mechanisms of known genetic defects in the hexosamine and CMP-sialic acid synthesis pathway in relation to the clinical phenotypes.
  
  
  CONCLUSIONS
  Both UDP-GlcNAc and CMP-sialic acid are important precursors for diverse protein glycosylation reactions and for conversion into other nucleotide-sugars. Defects in the synthesis of these nucleotide sugars might affect a wide range of protein glycosylation reactions. Involvement of multiple glycosylation pathways might contribute to disease phenotype, but the currently available biochemical information on sugar metabolism is insufficient to understand why defects in these pathways present with tissue-specific phenotypes.
  
  
  CONCLUSIONS
  Future research on the interplay between sugar metabolism and different glycosylation pathways in a tissue- and cell-specific manner will contribute to elucidation of disease mechanisms and will create new opportunities for therapeutic intervention. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc.
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboudumc Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Anke P
authors.initials: AP
authors.lastname: Willems
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Baziel G M
authors.initials: BG
authors.lastname: van Engelen
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboudumc Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands. Electronic address: Dirk.Lefeber@radboudumc.nl.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
mesh_terms: D000328:Adult; D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000235:genetics / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006031:Glycosylation; D006595:Hexosamines / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019158:N-Acetylneuraminic Acid / Q000235:genetics / Q000378:metabolism; D010733:Phosphoglucomutase / Q000235:genetics / Q000378:metabolism
chemical_list: D006023:Glycoproteins; D006595:Hexosamines; C497511:GFPT1 protein, human; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); C549916:PGM3 protein, human; D010733:Phosphoglucomutase; D019158:N-Acetylneuraminic Acid
keywords: Congenital disorders of glycosylation; GFPT1; GNE; Hexosamine biosynthesis pathway; PGM3; Sialic acid synthesis