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

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