TY - JOUR AU - Radenkovic, Silvia AU - Bird, Matthew J. AU - Emmerzaal, Tim L. AU - Wong, Sunnie Y. AU - Felgueira, Catarina AU - Stiers, Kyle M. AU - Sabbagh, Leila AU - Himmelreich, Nastassja AU - Poschet, Gernot AU - Windmolders, Petra AU - Verheijen, Jan AU - Witters, Peter AU - Altassan, Ruqaiah AU - Honzik, Tomas AU - Eminoglu, Tuba F. AU - James, Phillip M. AU - Edmondson, Andrew C. AU - Hertecant, Jozef AU - Kozicz, Tamás AU - Thiel, Christian AU - Vermeersch, Pieter AU - Cassiman, David AU - Beamer, Lesa AU - Morava-Kozicz, Éva AU - Ghesquiere, Bart TI - The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG JF - AMERICAN JOURNAL OF HUMAN GENETICS J2 - AM J HUM GENET VL - 104 PY - 2019 IS - 5 SP - 835 EP - 846 PG - 12 SN - 0002-9297 DO - 10.1016/j.ajhg.2019.03.003 UR - https://m2.mtmt.hu/api/publication/31535227 ID - 31535227 AB - Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA). On the basis of the decreased galactosylation in glycan chains, galactose was administered to individuals with PGM1-CDG and was shown to markedly reverse most disease-related laboratory abnormalities. The disease and treatment mechanisms, however, have remained largely elusive. Here, we confirm the clinical benefit of galactose supplementation in PGM1-CDG-affected individuals and obtain significant insights into the functional and biochemical regulation of glycosylation. We report here that, by using tracer-based metabolomics, we found that galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their sugar metabolism, and as such replenishes the depleted levels of galactose-1-P, as well as the levels of UDP-glucose and UDP-galactose, the nucleotide sugars that are required for ER- and GA-linked glycosylation, respectively. To this end, we further show that the galactose in UDP-galactose is incorporated into mature, de novo glycans. Our results also allude to the potential of monosaccharide therapy for several other CDG. LA - English DB - MTMT ER - TY - JOUR AU - Radenkovic, Silvia AU - Witters, Peter AU - Morava-Kozicz, Éva TI - Central nervous involvement is common in PGM1-CDG JF - MOLECULAR GENETICS AND METABOLISM J2 - MOL GENET METAB VL - 125 PY - 2018 IS - 3 SP - 200 EP - 204 PG - 5 SN - 1096-7192 DO - 10.1016/j.ymgme.2018.08.008 UR - https://m2.mtmt.hu/api/publication/31968105 ID - 31968105 AB - PGM1, the enzyme responsible for the reversible inter-conversion of glucose-1-P and glucose-6-P, is also involved in glycosylation, leading to a wide range of clinical manifestations, such as congenital malformations, hypoglycemia, hormonal dysregulation, myopathy, hepatopathy, and cardiomyopathy. So far, PGM1 deficiency has not been associated with central nervous system involvement or intellectual disability. Seizures and neurologic involvement in PGM1-CDG were thought to be a consequence of hypoglycemia. We reviewed all reported PGM1 deficient patients for the presence of the central nervous system involvement, their treatment and disease history. We detected 17 patients out of the 41 reported PGM1-CDG cases with significant neurologic involvement. Several of these patients had no severe hypoglycemic episodes, or were adequately treated for hypoglycemia with no recurrent episodes of low blood sugars, while one patient had no reported hypoglycemic episodes. We suggest that neurological symptoms are frequent in PGM1-CDG and could present even in the absence of hypoglycemia. The central nervous system should be assessed early on during the diagnostic process to optimize outcome in patients with PGM1-CDG. LA - English DB - MTMT ER - TY - JOUR 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 - Do, Nguyen David 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, Tamás AU - Morava-Kozicz, Éva TI - Oral D-galactose supplementation in PGM1-CDG JF - GENETICS IN MEDICINE J2 - GENET MED VL - 19 PY - 2017 IS - 11 SP - 1226 EP - 1235 PG - 10 SN - 1098-3600 DO - 10.1038/gim.2017.41 UR - https://m2.mtmt.hu/api/publication/31966950 ID - 31966950 AB - Purpose: Phosphoglucomutase-1 deficiency is a subtype of congenital disorders of glycosylation (PGM1-CDG). Previous case reports 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. LA - English DB - MTMT ER - TY - JOUR AU - Wong, Sunnie Yan-Wai AU - Beamer, Lesa J AU - Gadomski, Therese AU - Honzik, Tomas AU - Mohamed, Miski AU - Wortmann, Saskia B AU - Holmefjord, Katja S Brocke AU - Mork, Marit AU - Bowling, Francis AU - Sykut-Cegielska, Jolanta AU - Koch, Dieter AU - Ackermann, Amanda AU - Stanley, Charles A AU - Rymen, Daisy AU - Zeharia, Avraham AU - Al-Sayed, Moeen AU - Marquardt, Thomas AU - Jaeken, Jaak AU - Lefeber, Dirk AU - Conrad, Donald F AU - Kozicz, Tamás AU - Morava-Kozicz, Éva TI - Defining the Phenotype and Assessing Severity in Phosphoglucomutase-1 Deficiency JF - JOURNAL OF PEDIATRICS J2 - J PEDIATR VL - 175 PY - 2016 SP - 130 EP - + PG - 15 SN - 0022-3476 DO - 10.1016/j.jpeds.2016.04.021 UR - https://m2.mtmt.hu/api/publication/26212289 ID - 26212289 LA - English DB - MTMT ER - TY - JOUR AU - Morava-Kozicz, Éva TI - Galactose supplementation in phosphoglucomutase-1 deficiency; review and outlook for a novel treatable CDG JF - MOLECULAR GENETICS AND METABOLISM J2 - MOL GENET METAB VL - 112 PY - 2014 IS - 4 SP - 275 EP - 279 PG - 5 SN - 1096-7192 DO - 10.1016/j.ymgme.2014.06.002 UR - https://m2.mtmt.hu/api/publication/31968138 ID - 31968138 AB - 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 0.5-1 g/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. (C) 2014 Elsevier Inc. All rights reserved. LA - English DB - MTMT ER - TY - JOUR AU - Tegtmeyer, L. C. AU - Rust, S. AU - van, Scherpenzeel M. AU - Ng, B. G. AU - Losfeld, M. -E. AU - Timal, S. AU - Raymond, K. AU - He, P. AU - Ichikawa, M. AU - Veltman, J. AU - Huijben, K. AU - Shin, Y. S. AU - Sharma, V. AU - Adamowicz, M. AU - Lammens, M. AU - Reunert, J. AU - Witten, A. AU - Schrapers, E. AU - Matthijs, G. AU - Jaeken, J. AU - Rymen, D. AU - Stojkovic, T. AU - Laforet, P. AU - Petit, F. AU - Aumaitre, O. AU - Czarnowska, E. AU - Piraud, M. AU - Podskarbi, T. AU - Stanley, C. A. AU - Matalon, R. AU - Burda, P. AU - Seyyedi, S. AU - Debus, V. AU - Socha, P. AU - Sykut-Cegielska, J. AU - van, Spronsen F. AU - de, Meirleir L. AU - Vajro, P. AU - DeClue, T. AU - Ficicioglu, C. AU - Wada, Y. AU - Wevers, R. A. AU - Vanderschaeghe, D. AU - Callewaert, N. AU - Fingerhut, R. AU - van, Schaftingen E. AU - Freeze, H. H. AU - Morava-Kozicz, Éva AU - Lefeber, D. J. AU - Marquardt, T. TI - Multiple Phenotypes in Phosphoglucomutase 1 Deficiency JF - NEW ENGLAND JOURNAL OF MEDICINE J2 - NEW ENGL J MED VL - 370 PY - 2014 IS - 6 SP - 533 EP - 542 PG - 10 SN - 0028-4793 DO - 10.1056/NEJMoa1206605 UR - https://m2.mtmt.hu/api/publication/31968149 ID - 31968149 AB - BackgroundCongenital disorders of glycosylation are genetic syndromes that result in impaired glycoprotein production. We evaluated patients who had a novel recessive disorder of glycosylation, with a range of clinical manifestations that included hepatopathy, bifid uvula, malignant hyperthermia, hypogonadotropic hypogonadism, growth retardation, hypoglycemia, myopathy, dilated cardiomyopathy, and cardiac arrest. MethodsHomozygosity mapping followed by whole-exome sequencing was used to identify a mutation in the gene for phosphoglucomutase 1 (PGM1) in two siblings. Sequencing identified additional mutations in 15 other families. Phosphoglucomutase 1 enzyme activity was assayed on cell extracts. Analyses of glycosylation efficiency and quantitative studies of sugar metabolites were performed. Galactose supplementation in fibroblast cultures and dietary supplementation in the patients were studied to determine the effect on glycosylation. ResultsPhosphoglucomutase 1 enzyme activity was markedly diminished in all patients. Mass spectrometry of transferrin showed a loss of complete N-glycans and the presence of truncated glycans lacking galactose. Fibroblasts supplemented with galactose showed restoration of protein glycosylation and no evidence of glycogen accumulation. Dietary supplementation with galactose in six patients resulted in changes suggestive of clinical improvement. A new screening test showed good discrimination between patients and controls. ConclusionsPhosphoglucomutase 1 deficiency, previously identified as a glycogenosis, is also a congenital disorder of glycosylation. Supplementation with galactose leads to biochemical improvement in indexes of glycosylation in cells and patients, and supplementation with complex carbohydrates stabilizes blood glucose. A new screening test has been developed but has not yet been validated. (Funded by the Netherlands Organization for Scientific Research and others.) Two brothers with an undefined congenital disorder of glycosylation were found to have phosphoglucomutase 1 deficiency, which has previously been described as a glycogen storage disorder. Supplementation with galactose improves protein glycosylation in this disease. Protein N-glycosylation is a ubiquitous process in all organ systems. During N-glycosylation, glycan precursors are assembled from monosaccharide units and then covalently attached to asparagine residues in the nascent peptide chain of a protein (Figure 1). The protein-bound glycans undergo further processing to generate mature glycoproteins. Genetic defects in protein N-glycosylation, designated as congenital disorders of glycosylation, lead to multisystem disorders. Mutations of genes involved in N-glycosylation may affect either the biosynthesis of the glycan precursor (congenital disorder of glycosylation type I [CDG-I]) or the processing of the glycan after its attachment to the protein (congenital disorder of glycosylation type ... LA - English DB - MTMT ER - TY - JOUR AU - Timal, S AU - Hoischen, A AU - Lehle, L AU - Adamowicz, M AU - Huijben, K AU - Sykut-Cegielska, J AU - Paprocka, J AU - Jamroz, E AU - van Spronsen, FJ AU - Korner, C AU - Gilissen, C AU - Rodenburg, RJ AU - Eidhof, I AU - Van, den Heuvel L AU - Thiel, C AU - Wevers, RA AU - Morava-Kozicz, Éva AU - Veltman, J AU - Lefeber, DJ TI - Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing JF - HUMAN MOLECULAR GENETICS J2 - HUM MOL GENET VL - 21 PY - 2012 IS - 19 SP - 4151 EP - 4161 PG - 11 SN - 0964-6906 DO - 10.1093/hmg/dds123 UR - https://m2.mtmt.hu/api/publication/23034636 ID - 23034636 LA - English DB - MTMT ER -