Oral D-galactose supplementation in PGM1-CDG

• Published in: Genetics in medicine Vol. 19; no. 11; pp. 1226 - 1235
• Main Authors: Wong, Sunnie Yan-Wai, Gadomski, Therese, van Scherpenzeel, Monique, Honzik, Tomas, Hansikova, Hana, Holmefjord, Katja S Brocke, Mork, Marit, Bowling, Francis, Sykut-Cegielska, Jolanta, Koch, Dieter, Hertecant, Jozef, Preston, Graeme, Jaeken, Jaak, Peeters, Nicole, Perez, Stefanie, Nguyen, David Do, Crivelly, Kea, Emmerzaal, Tim, Gibson, K Michael, Raymond, Kimiyo, Abu Bakar, Nurulamin, Foulquier, Francois, Poschet, Gernot, Ackermann, Amanda M, He, Miao, Lefeber, Dirk J, Thiel, Christian, Kozicz, Tamas, Morava, Eva
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2017; Elsevier Limited; Nature Publishing Group
• Series: Genetics in Medicine. Official Journal of the American College of Medical Genetics
• Subjects: 631/208/1516; 631/443/319/1642; 692/700/459/1994; 692/700/565/2072; Administration, Oral; Adolescent; Biomedical and Life Sciences; Biomedicine; Blood Coagulation; Blood Glucose - metabolism; Chemical Sciences; Child; Child, Preschool; Creatine Kinase - blood; Dose-Response Relationship, Drug; Female; Galactose - administration & dosage; Galactose - adverse effects; Galactose - therapeutic use; Glycogen Storage Disease - drug therapy; Glycoproteins - metabolism; Human Genetics; Humans; Infant; Laboratory Medicine; Male; or physical chemistry; original-research-article; Phosphoglucomutase - metabolism; Pilot Projects; Prospective Studies; Skin - cytology; Skin - metabolism; Studies; Theoretical and; Transferrin - metabolism; Young Adult; d-galactose; transferrin glycoforms; glycomics; phosphoglucomutase 1; antithrombin III; glycosylation; coagulation; LLO; endocrine; liver function; Drug; Administration; Creatine Kinase; Transferrin; Prospective Studies; Humans; Glycoprotein; Preschool; Male; Infant; Blood Glucose; Oral; Phosphoglucomutase; Young Adult; Pilot Projects; Adolescent; Blood Coagulation; Female; Dose-Response Relationship; Skin; Galactose; Child; Glycogen Storage Disease
• ISSN: 1098-3600; 1530-0366
• DOI: 10.1038/gim.2017.41

Purpose Phosphoglucomutase-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. Methods D -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 . Results Eight 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. Conclusion Oral 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.