Dataset Information

Oral D-galactose supplementation in PGM1-CDG.

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.

SUBMITTER: Wong SY

PROVIDER: S-EPMC5675745 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Oral D-galactose supplementation in PGM1-CDG.

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

Genetics in medicine : official journal of the American College of Medical Genetics 20170615 11

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 incre ...[more]

PMID: 28617415

Similar Datasets

Project description:ContextTMEM165 deficiency is a severe multisystem disease that manifests with metabolic, endocrine, and skeletal involvement. It leads to one type of congenital disorders of glycosylation (CDG), a rapidly growing group of inherited diseases in which the glycosylation process is altered. Patients have decreased galactosylation by serum glycan analysis. There are >100 CDGs, but only specific types are treatable.ObjectiveGalactose has been shown to be beneficial in other CDG types with abnormal galactosylation. The aim of this study was to characterize the effects of galactose supplementation on Golgi glycosylation in TMEM165-depleted HEK293 cells, as well as in 2 patients with TMEM165-CDG and in their cultured skin fibroblast cells.Design and settingGlycosylation was assessed by mass spectrometry, western blot analysis, and transferrin isoelectrofocusing.Patients and interventionsBoth unrelated patients with TMEM165-CDG with the same deep intronic homozygous mutation (c.792+182G>A) were allocated to receive d-galactose in a daily dose of 1 g/kg.ResultsWe analyzed N-linked glycans and glycolipids in knockout TMEM165 HEK293 cells, revealing severe hypogalactosylation and GalNAc transfer defects. Although these defects were completely corrected by the addition of Mn2+, we demonstrated that the observed N-glycosylation defect could also be overcome by galactose supplementation. We then demonstrated that oral galactose supplementation in patients with TMEM165-deficient CDG improved biochemical and clinical parameters, including a substantial increase in the negatively charged transferrin isoforms, and a decrease in hypogalactosylated total N-glycan structures, endocrine function, and coagulation parameters.ConclusionTo our knowledge, this is the first description of abnormal glycosylation of lipids in the TMEM165 defect and the first report of successful dietary treatment in TMEM165 deficiency. We recommend the use of oral d-galactose therapy in TMEM165-CDG.

Project description:We recently redefined phosphoglucomutase-1 deficiency not only as an enzyme defect, involved in normal glycogen metabolism, but also an inborn error of protein glycosylation. Phosphoglucomutase-1 is a key enzyme in glycolysis and glycogenesis by catalyzing in the bidirectional transfer of phosphate from position 1 to 6 on glucose. Glucose-1-P and UDP-glucose are closely linked to galactose metabolism. Normal PGM1 activity is important for effective glycolysis during fasting. Activated glucose and galactose are essential for normal protein glycosylation. The complex defect involving abnormal concentrations of activated sugars leads to hypoglycemia and two major phenotypic presentations, one with primary muscle involvement and the other with severe multisystem disease. The multisystem phenotype includes growth delay and malformations, like cleft palate or uvula, and liver, endocrine and heart function with possible cardiomyopathy. The patients have normal intelligence. Decreased transferrin galactosylation is a characteristic finding on mass spectrometry. Previous in vitro studies in patient fibroblasts showed an improvement of glycosylation on galactose supplements. Four patients with PGM1 deficiency have been trialed on d-galactose (compassionate use), and showed improvement of serum transferrin hypoglycosylation. There was a parallel improvement of liver function, endocrine abnormalities and a decrease in the frequency of hypoglycemic episodes. No side effects have been observed. Galactose supplementation didn't seem to resolve all clinical symptoms. Adding complex carbohydrates showed an additional clinical amelioration. Based on the available clinical data we suggest to consider the use of 0.5-1g/kg/day d-galactose and maximum 50 g/day oral galactose therapy in PGM1-CDG. The existing data on galactose therapy have to be viewed as preliminary observations. A prospective multicenter trial is ongoing to evaluate the efficacy and optimal d-galactose dose of galactose supplementation.

Dataset Information

Oral D-galactose supplementation in PGM1-CDG.

Publications

Oral D-galactose supplementation in PGM1-CDG.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets