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 & 9 others Nurulamin Abu Bakar, Francois Foulquier, Gernot Poschet, Amanda M. Ackermann, Miao He, Dirk J. Lefeber, Christian Thiel, Tamas Kozicz, Eva Morava-Kozicz

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1226-1235
Number of pages10
JournalGenetics in Medicine
Volume19
Issue number11
DOIs
StatePublished - Nov 1 2017
Externally publishedYes

Fingerprint

Galactose
Glycosylation
Transferrin
Polysaccharides
Uridine Diphosphate
Congenital Disorders of Glycosylation
Safety
Antithrombin III
Partial Thromboplastin Time
Therapeutics
Aspartate Aminotransferases
Alanine Transaminase
Nucleotides
Fibroblasts
Prospective Studies
Liver
Serum

Keywords

  • coagulation
  • glycomics
  • glycosylation
  • LLO
  • phosphoglucomutase 1

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Wong, S. Y. W., Gadomski, T., Van Scherpenzeel, M., Honzik, T., Hansikova, H., Holmefjord, K. S. B., ... Morava-Kozicz, E. (2017). Oral D-galactose supplementation in PGM1-CDG. Genetics in Medicine, 19(11), 1226-1235. https://doi.org/10.1038/gim.2017.41

Oral D-galactose supplementation in PGM1-CDG. / 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-Kozicz, Eva.

In: Genetics in Medicine, Vol. 19, No. 11, 01.11.2017, p. 1226-1235.

Research output: Contribution to journalArticle

Wong, SYW, Gadomski, T, Van Scherpenzeel, M, Honzik, T, Hansikova, H, Holmefjord, KSB, Mork, M, Bowling, F, Sykut-Cegielska, J, Koch, D, Hertecant, J, Preston, G, Jaeken, J, Peeters, N, Perez, S, Nguyen, DD, Crivelly, K, Emmerzaal, T, Gibson, KM, Raymond, K, Abu Bakar, N, Foulquier, F, Poschet, G, Ackermann, AM, He, M, Lefeber, DJ, Thiel, C, Kozicz, T & Morava-Kozicz, E 2017, 'Oral D-galactose supplementation in PGM1-CDG', Genetics in Medicine, vol. 19, no. 11, pp. 1226-1235. https://doi.org/10.1038/gim.2017.41
Wong SYW, Gadomski T, Van Scherpenzeel M, Honzik T, Hansikova H, Holmefjord KSB et al. Oral D-galactose supplementation in PGM1-CDG. Genetics in Medicine. 2017 Nov 1;19(11):1226-1235. https://doi.org/10.1038/gim.2017.41
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-Kozicz, Eva. / Oral D-galactose supplementation in PGM1-CDG. In: Genetics in Medicine. 2017 ; Vol. 19, No. 11. pp. 1226-1235.
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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.",
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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-Kozicz, Eva

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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.

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KW - glycomics

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KW - LLO

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