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Multiple phenotypes in phosphoglucomutase 1 deficiency

(2014) NEW ENGLAND JOURNAL OF MEDICINE. 370(6). p.533-542
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Abstract
Background: 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. Methods: 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. Results: 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. Conclusions: 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.) 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
MUSCLE GLYCOGENOSIS, DILATED CARDIOMYOPATHY, NUCLEOTIDE SUGARS, GLYCOSYLATION, IDENTIFICATION, CHILDREN, THERAPY, GLUCOSE, CONGENITAL DISORDERS, GLYCOGEN-STORAGE-DISEASE

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Chicago
Tegtmeyer, LC, S Rust, M van Scherpenzeel, BG Ng, ME Losfeld, S Timal, K Raymond, et al. 2014. “Multiple Phenotypes in Phosphoglucomutase 1 Deficiency.” New England Journal of Medicine 370 (6): 533–542.
APA
Tegtmeyer, L., Rust, S., van Scherpenzeel, M., Ng, B., Losfeld, M., Timal, S., Raymond, K., et al. (2014). Multiple phenotypes in phosphoglucomutase 1 deficiency. NEW ENGLAND JOURNAL OF MEDICINE, 370(6), 533–542.
Vancouver
1.
Tegtmeyer L, Rust S, van Scherpenzeel M, Ng B, Losfeld M, Timal S, et al. Multiple phenotypes in phosphoglucomutase 1 deficiency. NEW ENGLAND JOURNAL OF MEDICINE. 2014;370(6):533–42.
MLA
Tegtmeyer, LC, S Rust, M van Scherpenzeel, et al. “Multiple Phenotypes in Phosphoglucomutase 1 Deficiency.” NEW ENGLAND JOURNAL OF MEDICINE 370.6 (2014): 533–542. Print.
@article{4349577,
  abstract     = {Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.)
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 ...},
  author       = {Tegtmeyer, LC and Rust, S and van Scherpenzeel, M and Ng, BG and Losfeld, ME and Timal, S and Raymond, K and He, P and Ichikawa, M and Veltman, J and Huijben, K and Shin, YS 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, CA 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, RA and Vanderschaeghe, Dieter and Callewaert, Nico and Fingerhut, R and van Schaftingen, E and Freeze, HH and Morava, E and Lefeber, DJ and Marquardt, T},
  issn         = {0028-4793},
  journal      = {NEW ENGLAND JOURNAL OF MEDICINE},
  language     = {eng},
  number       = {6},
  pages        = {533--542},
  title        = {Multiple phenotypes in phosphoglucomutase 1 deficiency},
  url          = {http://dx.doi.org/10.1056/NEJMoa1206605},
  volume       = {370},
  year         = {2014},
}

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