Oral D-galactose supplementation in PGM1-CDG.

Sunnie Yan-Wai Wong, Therese Gadomski, Monique van Scherpenzeel, Tomas Honzik, Hana Hansikova, Katja S Brocke Holmefjord, Marit Mork, Francis Bowling, Jolanta Sykut-Cegielska, Dieter Koch, Jozef Hertecant, Graeme Preston, Jaak Jaeken, Nicole Peeters, Stefanie Perez, David Do Nguyen, Kea Crivelly, Tim Emmerzaal, K Michael Gibson, Kimiyo Raymond, Nurulamin Abu Bakar, Francois Foulquier, Gernot Poschet, Amanda M Ackermann, Miao He, Dirk J Lefeber, Christian Thiel, Tamas Kozicz, Eva Morava

Journal: Genetics in medicine : official journal of the American College of Medical Genetics 2018;19(11):1226-1235

PMID: 28617415

Abstract

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.

Address: Hayward Genetics Center, Tulane University School of Medicine, New Orleans, Louisiana, USA.; Department of Neurology, Translational Metabolic Laboratory, Donders Institute for Brain, Cognition, and Behavior, Radboudumc, Nijmegen, The Netherlands.; Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.; Department of Pediatric Habilitation, Stavanger University Hospital, Stavanger, Norway.; Biochemical Diseases, Mater Children's Hospital, South, Brisbane, Queensland, Australia.; Screening and Metabolic Diagnostics Department, The Institute of Mother and Child, Warsaw, Poland.; Pediatric Cardiology, Bergisch Gladbacher Koln, Koln, Germany.; Genetics/Metabolics Service, Tawam Hospital, Al Ain, United Arab Emirates.; Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.; Department of Anatomy, Radboud University Medical Centre, Nijmegen, The Netherlands.; Washington State University College of Pharmacy, Spokane, Washington, USA.; Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.; University Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France.; Centre for Organismal Studies (COS), University of Heidelberg, Heidelberg, Germany.; Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.; Palmieri Metabolic Disease Laboratory, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.; Center for Child and Adolescent Medicine, Kinderheilkunde I, University of Heidelberg, Heidelberg, Germany.; Hayward Genetics Center, Tulane University School of Medicine, New Orleans, Louisiana, USA.; Department of Anatomy, Radboud University Medical Centre, Nijmegen, The Netherlands.
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