TY - JOUR
T1 - Oral D-galactose supplementation in PGM1-CDG
AU - Wong, Sunnie Yan Wai
AU - Gadomski, Therese
AU - Van Scherpenzeel, Monique
AU - Honzik, Tomas
AU - Hansikova, Hana
AU - Holmefjord, Katja S.Brocke
AU - Mork, Marit
AU - Bowling, Francis
AU - Sykut-Cegielska, Jolanta
AU - Koch, Dieter
AU - Hertecant, Jozef
AU - Preston, Graeme
AU - Jaeken, Jaak
AU - Peeters, Nicole
AU - Perez, Stefanie
AU - Nguyen, David Do
AU - Crivelly, Kea
AU - Emmerzaal, Tim
AU - Gibson, K. Michael
AU - Raymond, Kimiyo
AU - Abu Bakar, Nurulamin
AU - Foulquier, Francois
AU - Poschet, Gernot
AU - Ackermann, Amanda M.
AU - He, Miao
AU - Lefeber, Dirk J.
AU - Thiel, Christian
AU - Kozicz, Tamas
AU - Morava, Eva
N1 - Funding Information:
This study is supported in part by the Hayward Foundation and by 1 U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health, which funds the Louisiana Clinical and Translational Science Center. Additional support comes from the European Union's Horizon 2020 research and innovation program under the ERA-Net for Research on Rare Diseases, from the Netherlands Organisation for Scientific Research (ZONMW Medium Investment grant 40-00506-98-9001 and VIDI grant 91713359 to D.J.L., VENI grant 016168079 to M.v.S.) and the Prinses Beatrix Spierfonds (grant W.OR15-16 to D.J.L. and M.v.S.). T.H. and H.H. was supported by General University Hospital in Prague, Czech Republic (RVO-VFN 64165), and the Ministry of Health of the Czech Republic (MZ CR AZV 16-31932A). We thank the patients and their families for their participation. EM and CT this work was supported by the European Union's Horizon 2020 research and innovation program under the ERA-NET Cofund action N° 643578 – EURO-CDG-2 and for CT sustained by the German Bundesministerium fuer Bildung und Forschung under the frame of E-Rare-3. We are also grateful to Hudson Freeze at the Burnham Institute (San Diego, CA) for sharing a patient cell line with us. We also thank for the trial support by Jos Dederen.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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.
AB - 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.
KW - LLO
KW - coagulation
KW - glycomics
KW - glycosylation
KW - phosphoglucomutase 1
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U2 - 10.1038/gim.2017.41
DO - 10.1038/gim.2017.41
M3 - Article
C2 - 28617415
AN - SCOPUS:85029661973
SN - 1098-3600
VL - 19
SP - 1226
EP - 1235
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 11
ER -