Dataset Information

Multiple phenotypes in phosphoglucomutase 1 deficiency.

ABSTRACT: Congenital 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.Homozygosity 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.Phosphoglucomutase 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.Phosphoglucomutase 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.).

SUBMITTER: Tegtmeyer LC

PROVIDER: S-EPMC4373661 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Multiple phenotypes in phosphoglucomutase 1 deficiency.

Tegtmeyer Laura C LC Rust Stephan S van Scherpenzeel Monique M Ng Bobby G BG Losfeld Marie-Estelle ME Timal Sharita S Raymond Kimiyo K He Ping P Ichikawa Mie M Veltman Joris J Huijben Karin K Shin Yoon S YS Sharma Vandana V Adamowicz Maciej M Lammens Martin M Reunert Janine J Witten Anika A Schrapers Esther E Matthijs Gert G Jaeken Jaak J Rymen Daisy D Stojkovic Tanya T Laforêt Pascal P Petit François F Aumaître Olivier O Czarnowska Elzbieta E Piraud Monique M Podskarbi Teodor T Stanley Charles A CA Matalon Reuben R Burda Patricie P Seyyedi Soraya S Debus Volker V Socha Piotr P Sykut-Cegielska Jolanta J van Spronsen Francjan F de Meirleir Linda L Vajro Pietro P DeClue Terry T Ficicioglu Can C Wada Yoshinao Y Wevers Ron A RA Vanderschaeghe Dieter D Callewaert Nico N Fingerhut Ralph R van Schaftingen Emile E Freeze Hudson H HH Morava Eva E Lefeber Dirk J DJ Marquardt Thorsten T

The New England journal of medicine 20140201 6

<h4>Background</h4>Congenital 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.<h4>Methods</h4>Homozygosity mapping followed by whole-exome sequencing was ...[more]

PMID: 24499211

Similar Datasets

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

Multiple phenotypes in phosphoglucomutase 1 deficiency.

Publications

Multiple phenotypes in phosphoglucomutase 1 deficiency.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets