PurposePhosphoglucomutase-1 deficiency is a subtype of congenital disorders of glycosylation (PGM1-CDG). Previous casereports in PGM1-CDG patients receiving oral D-galactose (D-gal) showed clinical improvement. So far no systematic in vitro and clinical studies have assessed safety and benefits of D-gal supplementation. In a prospective pilot study, we evaluated the effects of oral D-gal in nine patients.MethodsD-gal supplementation was increased to 1.5 g/kg/day (maximum 50 g/day) in three increments over 18 weeks. Laboratory studies were performed before and during treatment to monitor safety and effect on serum transferrin-glycosylation, coagulation, and liver and endocrine function. Additionally, the effect of D-gal on cellular glycosylation was characterized in vitro.ResultsEight patients were compliant with D-gal supplementation. No adverse effects were reported. Abnormal baseline results (alanine transaminase, aspartate transaminase, activated partial thromboplastin time) improved or normalized already using 1 g/kg/day D-gal. Antithrombin-III levels and transferrin-glycosylation showed significant improvement, and increase in galactosylation and whole glycan content. In vitro studies before treatment showed N-glycan hyposialylation, altered O-linked glycans, abnormal lipid-linked oligosaccharide profile, and abnormal nucleotide sugars in patient fibroblasts. Most cellular abnormalities improved or normalized following D-gal treatment. D-gal increased both UDP-Glc and UDP-Gal levels and improved lipid-linked oligosaccharide fractions in concert with improved glycosylation in PGM1-CDG.ConclusionOral D-gal supplementation is a safe and effective treatment for PGM1-CDG in this pilot study. Transferrin glycosylation and ATIII levels were useful trial end points. Larger, longer-duration trials are ongoing.

Biochemical Diseases Mater Children's Hospital South Brisbane Queensland Australia

Center for Child and Adolescent Medicine Kinderheilkunde 1 University of Heidelberg Heidelberg Germany

Centre for Organismal Studies University of Heidelberg Heidelberg Germany

Department of Anatomy Radboud University Medical Centre Nijmegen The Netherlands

Department of Neurology Translational Metabolic Laboratory Donders Institute for Brain Cognition and Behavior Radboudumc Nijmegen The Netherlands

Department of Pediatric Habilitation Stavanger University Hospital Stavanger Norway

Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Prague Czech Republic

Department of Pediatrics University Hospitals Leuven Leuven Belgium

Division of Endocrinology and Diabetes The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA

Division of Laboratory Genetics Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota USA

Genetics Metabolics Service Tawam Hospital Al Ain United Arab Emirates

Hayward Genetics Center Tulane University School of Medicine New Orleans Louisiana USA

Palmieri Metabolic Disease Laboratory The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA

Pediatric Cardiology Bergisch Gladbacher Koln Koln Germany

Screening and Metabolic Diagnostics Department The Institute of Mother and Child Warsaw Poland

University Lille CNRS UMR 8576 UGSF Unité de Glycobiologie Structurale et Fonctionnelle Lille France

Washington State University College of Pharmacy Spokane Washington USA

Zobrazit více v PubMed

Jaeken J. Congenital disorders of glycosylation (CDG): it’s (nearly) all in it! J Inherit Metab Dis. 2011;34(4):853–858. PubMed

Timal S, Hoischen A, Lehle L, et al. Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing. Hum Mol Genet. 2012;21(19):4151–4161. PubMed

Tegtmeyer LC, Rust S, van Scherpenzeel M, et al. Multiple phenotypes in phosphoglucomutase 1 deficiency. N Engl J Med. 2014;370(6):533–542. PubMed PMC

Wong SY-W, Beamer LJ, Gadomski T, et al. Defining the Phenotype and Assessing Severity in Phosphoglucomutase-1 Deficiency. J Pediatr. 2016 May; doi: 10.1016/j.jpeds.2016.04.021.. PubMed DOI

Morava E. Galactose supplementation in phosphoglucomutase-1 deficiency; review and outlook for a novel treatable CDG. Mol Genet Metab. 2014;112(4):275–279. PubMed PMC

Stojkovic T, Vissing J, Petit F, et al. Muscle glycogenosis due to phosphoglucomutase 1 deficiency. N Engl J Med. 2009;361(4):425–427. PubMed

Beamer LJ. Mutations in hereditary phosphoglucomutase 1 deficiency map to key regions of enzyme structure and function. J Inherit Metab Dis. 2014 Aug; doi: 10.1007/s10545-014-9757-9.. PubMed DOI

Lee Y, Stiers KM, Kain BN, Beamer LJ. Compromised catalysis and potential folding defects in in vitro studies of missense mutants associated with hereditary phosphoglucomutase 1 deficiency. J Biol Chem. 2014;289(46):32010–32019. PubMed PMC

De Smet E, Rioux J-P, Ammann H, Déziel C, Quérin S. FSGS permeability factor-associated nephrotic syndrome: remission after oral galactose therapy. Nephrol Dial Transplant. 2009;24(9):2938–2940. PubMed

van Scherpenzeel M, Steenbergen G, Morava E, Wevers RA, Lefeber DJ. High-resolution mass spectrometry glycoprofiling of intact transferrin for diagnosis and subtype identification in the congenital disorders of glycosylation. Transl Res. 2015;166(6):639–649. e1. PubMed

Thiel C, Schwarz M, Peng J, et al. A new type of congenital disorders of glycosylation (CDG-Ii) provides new insights into the early steps of dolichol-linked oligosaccharide biosynthesis. J Biol Chem. 2003;278(25):22498–22505. PubMed

Kochanowski N, Blanchard F, Cacan R, et al. Intracellular nucleotide and nucleotide sugar contents of cultured CHO cells determined by a fast, sensitive, and high-resolution ion-pair RP-HPLC. Anal Biochem. 2006;348(2):243–251. PubMed

Xia B, Zhang W, Li X, et al. Serum N-glycan and O-glycan analysis by mass spectrometry for diagnosis of congenital disorders of glycosylation. Anal Biochem. 2013;442(2):178–185. PubMed

Niehues R, Hasilik M, Alton G, et al. Carbohydrate-deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy. J Clin Invest. 1998;101(7):1414–1420. PubMed PMC

Ichikawa M, Scott DA, Losfeld M-E, Freeze HH. The metabolic origins of mannose in glycoproteins. J Biol Chem. 2014;289(10):6751–6761. PubMed PMC

Freeze HH. Perhaps a wee bit of sugar would help. Nat Genet. 2016;48(7):705–707. PubMed PMC

Scott K, Gadomski T, Kozicz T, Morava E. Congenital disorders of glycosylation: new defects and still counting. J Inherit Metab Dis. 2014;37(4):609–617. PubMed PMC

Körner C, Knauer R, Holzbach U, Hanefeld F, Lehle L, von Figura K. Carbohydrate-deficient glycoprotein syndrome type V: deficiency of dolichyl-P-Glc:Man9GlcNAc2-PP-dolichyl glucosyltransferase. Proc Natl Acad Sci U S A. 1998;95(22):13200–13205. PubMed PMC

Chantret I, Dancourt J, Dupré T, et al. A deficiency in dolichyl-P-glucose:Glc1Man9GlcNAc2-PP-dolichyl alpha3-glucosyltransferase defines a new subtype of congenital disorders of glycosylation. J Biol Chem. 2003;278(11):9962–9971. PubMed

Kranz C, Denecke J, Lehrman MA, et al. A mutation in the human MPDU1 gene causes congenital disorder of glycosylation type If (CDG-If) J Clin Invest. 2001;108(11):1613–1619. PubMed PMC

Schenk B, Imbach T, Frank CG, et al. MPDU1 mutations underlie a novel human congenital disorder of glycosylation, designated type If. J Clin Invest. 2001;108(11):1687–1695. PubMed PMC

Maliekal P, et al. Molecular identification of mammalian phosphopentomutase and glucose-1,6-bisphosphate synthase, two members of the alpha-D-phosphohexomutase family. The Journal of biological chemistry. 2007;282(44):31844–31851. PubMed

Ondruskova N, et al. Glycogen storage disease-like phenotype with central nervous system involvement in a PGM1-CDG patient. Neuro endocrinology letters. 2014;35(2):137–141. PubMed

Tegtmeyer LC, et al. Multiple phenotypes in phosphoglucomutase 1 deficiency. The New England journal of medicine. 2014;370(6):533–542. PubMed PMC

Wong SY-W, et al. Defining the Phenotype and Assessing Severity in Phosphoglucomutase-1 Deficiency. The Journal of pediatrics. 2016 Available at: http://dx.doi.org/10.1016/j.jpeds.2016.04.021. PubMed DOI

International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management

The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG

Intact transferrin and total plasma glycoprofiling for diagnosis and therapy monitoring in phosphoglucomutase-I deficiency