@article{MTMT:31535227,
	title = {The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG},
	url = {https://m2.mtmt.hu/api/publication/31535227},
	author = {Radenkovic, Silvia and Bird, Matthew J. and Emmerzaal, Tim L. and Wong, Sunnie Y. and Felgueira, Catarina and Stiers, Kyle M. and Sabbagh, Leila and Himmelreich, Nastassja and Poschet, Gernot and Windmolders, Petra and Verheijen, Jan and Witters, Peter and Altassan, Ruqaiah and Honzik, Tomas and Eminoglu, Tuba F. and James, Phillip M. and Edmondson, Andrew C. and Hertecant, Jozef and Kozicz, Tamás and Thiel, Christian and Vermeersch, Pieter and Cassiman, David and Beamer, Lesa and Morava-Kozicz, Éva and Ghesquiere, Bart},
	doi = {10.1016/j.ajhg.2019.03.003},
	journal-iso = {AM J HUM GENET},
	journal = {AMERICAN JOURNAL OF HUMAN GENETICS},
	volume = {104},
	unique-id = {31535227},
	issn = {0002-9297},
	abstract = {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.},
	year = {2019},
	eissn = {1537-6605},
	pages = {835-846},
	orcid-numbers = {Radenkovic, Silvia/0000-0001-8190-7736; Verheijen, Jan/0000-0003-0481-9649; Vermeersch, Pieter/0000-0001-7076-061X; Cassiman, David/0000-0002-6154-0970; Ghesquiere, Bart/0000-0003-1547-1705}
}

@article{MTMT:31968105,
	title = {Central nervous involvement is common in PGM1-CDG},
	url = {https://m2.mtmt.hu/api/publication/31968105},
	author = {Radenkovic, Silvia and Witters, Peter and Morava-Kozicz, Éva},
	doi = {10.1016/j.ymgme.2018.08.008},
	journal-iso = {MOL GENET METAB},
	journal = {MOLECULAR GENETICS AND METABOLISM},
	volume = {125},
	unique-id = {31968105},
	issn = {1096-7192},
	abstract = {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.},
	keywords = {SEIZURES; hypoglycemia; glycosylation; intellectual disability; Endocrinology & Metabolism; developmental delay; Genetics & Heredity; CDG; congenital disorders; phosphoglucomutase 1 deficiency; Phosphoglucomutase 1},
	year = {2018},
	eissn = {1096-7206},
	pages = {200-204},
	orcid-numbers = {Radenkovic, Silvia/0000-0001-8190-7736; Witters, Peter/0000-0002-9264-6153}
}

@article{MTMT:31966950,
	title = {Oral D-galactose supplementation in PGM1-CDG},
	url = {https://m2.mtmt.hu/api/publication/31966950},
	author = {Wong, Sunnie Yan-Wai and Gadomski, Therese and van, Scherpenzeel Monique and Honzik, Tomas and Hansikova, Hana and Holmefjord, Katja S. Brocke and Mork, Marit and Bowling, Francis and Sykut-Cegielska, Jolanta and Koch, Dieter and Hertecant, Jozef and Preston, Graeme and Jaeken, Jaak and Peeters, Nicole and Perez, Stefanie and Do, Nguyen David and Crivelly, Kea and Emmerzaal, Tim and Gibson, K. Michael and Raymond, Kimiyo and Abu, Bakar Nurulamin and Foulquier, Francois and Poschet, Gernot and Ackermann, Amanda M. and He, Miao and Lefeber, Dirk J. and Thiel, Christian and Kozicz, Tamás and Morava-Kozicz, Éva},
	doi = {10.1038/gim.2017.41},
	journal-iso = {GENET MED},
	journal = {GENETICS IN MEDICINE},
	volume = {19},
	unique-id = {31966950},
	issn = {1098-3600},
	abstract = {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.},
	keywords = {MASS-SPECTROMETRY; IDENTIFICATION; PHENOTYPE; COAGULATION; diagnosis; glycosylation; glycosylation; mannose; glycomics; CDG; congenital disorders; LLO; phosphoglucomutase 1 deficiency},
	year = {2017},
	eissn = {1530-0366},
	pages = {1226-1235},
	orcid-numbers = {Gadomski, Therese/0000-0003-3286-9942; Hansikova, Hana/0000-0002-2734-225X; Sykut-Cegielska, Jolanta/0000-0003-0762-3721; Emmerzaal, Tim/0000-0002-5066-0221; Abu, Bakar Nurulamin/0000-0001-6818-7973}
}

@article{MTMT:26212289,
	title = {Defining the Phenotype and Assessing Severity in Phosphoglucomutase-1 Deficiency},
	url = {https://m2.mtmt.hu/api/publication/26212289},
	author = {Wong, Sunnie Yan-Wai and Beamer, Lesa J and Gadomski, Therese and Honzik, Tomas and Mohamed, Miski and Wortmann, Saskia B and Holmefjord, Katja S Brocke and Mork, Marit and Bowling, Francis and Sykut-Cegielska, Jolanta and Koch, Dieter and Ackermann, Amanda and Stanley, Charles A and Rymen, Daisy and Zeharia, Avraham and Al-Sayed, Moeen and Marquardt, Thomas and Jaeken, Jaak and Lefeber, Dirk and Conrad, Donald F and Kozicz, Tamás and Morava-Kozicz, Éva},
	doi = {10.1016/j.jpeds.2016.04.021},
	journal-iso = {J PEDIATR},
	journal = {JOURNAL OF PEDIATRICS},
	volume = {175},
	unique-id = {26212289},
	issn = {0022-3476},
	year = {2016},
	eissn = {1097-6833},
	pages = {130-+}
}

@article{MTMT:31968138,
	title = {Galactose supplementation in phosphoglucomutase-1 deficiency; review and outlook for a novel treatable CDG},
	url = {https://m2.mtmt.hu/api/publication/31968138},
	author = {Morava-Kozicz, Éva},
	doi = {10.1016/j.ymgme.2014.06.002},
	journal-iso = {MOL GENET METAB},
	journal = {MOLECULAR GENETICS AND METABOLISM},
	volume = {112},
	unique-id = {31968138},
	issn = {1096-7192},
	abstract = {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.},
	keywords = {hypoglycemia; glycosylation; GALACTOSE; glycogenolysis; Endocrinology & Metabolism; Genetics & Heredity; CDG; Muscle glycogenosis; PGM1},
	year = {2014},
	eissn = {1096-7206},
	pages = {275-279}
}

@article{MTMT:31968149,
	title = {Multiple Phenotypes in Phosphoglucomutase 1 Deficiency},
	url = {https://m2.mtmt.hu/api/publication/31968149},
	author = {Tegtmeyer, L. C. and Rust, S. and van, Scherpenzeel M. and Ng, B. G. and Losfeld, M. -E. and Timal, S. and Raymond, K. and He, P. and Ichikawa, M. and Veltman, J. and Huijben, K. and Shin, Y. S. and Sharma, V. and Adamowicz, M. and Lammens, M. and Reunert, J. and Witten, A. and Schrapers, E. and Matthijs, G. and Jaeken, J. and Rymen, D. and Stojkovic, T. and Laforet, P. and Petit, F. and Aumaitre, O. and Czarnowska, E. and Piraud, M. and Podskarbi, T. and Stanley, C. A. and Matalon, R. and Burda, P. and Seyyedi, S. and Debus, V. and Socha, P. and Sykut-Cegielska, J. and van, Spronsen F. and de, Meirleir L. and Vajro, P. and DeClue, T. and Ficicioglu, C. and Wada, Y. and Wevers, R. A. and Vanderschaeghe, D. and Callewaert, N. and Fingerhut, R. and van, Schaftingen E. and Freeze, H. H. and Morava-Kozicz, Éva and Lefeber, D. J. and Marquardt, T.},
	doi = {10.1056/NEJMoa1206605},
	journal-iso = {NEW ENGL J MED},
	journal = {NEW ENGLAND JOURNAL OF MEDICINE},
	volume = {370},
	unique-id = {31968149},
	issn = {0028-4793},
	abstract = {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 ...},
	keywords = {IDENTIFICATION; CHILDREN; Therapy; glycosylation; DILATED CARDIOMYOPATHY; congenital disorders; Muscle glycogenosis; GLYCOGEN-STORAGE-DISEASE; Nucleotide sugars},
	year = {2014},
	eissn = {1533-4406},
	pages = {533-542}
}

@article{MTMT:23034636,
	title = {Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing},
	url = {https://m2.mtmt.hu/api/publication/23034636},
	author = {Timal, S and Hoischen, A and Lehle, L and Adamowicz, M and Huijben, K and Sykut-Cegielska, J and Paprocka, J and Jamroz, E and van Spronsen, FJ and Korner, C and Gilissen, C and Rodenburg, RJ and Eidhof, I and Van, den Heuvel L and Thiel, C and Wevers, RA and Morava-Kozicz, Éva and Veltman, J and Lefeber, DJ},
	doi = {10.1093/hmg/dds123},
	journal-iso = {HUM MOL GENET},
	journal = {HUMAN MOLECULAR GENETICS},
	volume = {21},
	unique-id = {23034636},
	issn = {0964-6906},
	year = {2012},
	eissn = {1460-2083},
	pages = {4151-4161}
}