Multiple phenotypes in phosphoglucomutase 1 deficiency

L. C. Tegtmeyer, S. Rust, M. Van Scherpenzeel, B. G. Ng, M. E. Losfeld, S. Timal, K. Raymond, P. He, M. Ichikawa, J. Veltman, K. Huijben, Y. S. Shin, V. Sharma, M. Adamowicz, M. Lammens, J. Reunert, A. Witten, E. Schrapers, G. Matthijs, J. Jaeken & 30 others D. Rymen, T. Stojkovic, P. Laforêt, F. Petit, O. Aumaître, E. Czarnowska, M. Piraud, T. Podskarbi, C. A. Stanley, Reuben Matalon, P. Burda, S. Seyyedi, V. Debus, P. Socha, J. Sykut-Cegielska, F. Van Spronsen, L. De Meirleir, P. Vajro, T. DeClue, C. Ficicioglu, Y. Wada, R. A. Wevers, D. Vanderschaeghe, N. Callewaert, R. Fingerhut, E. Van Schaftingen, H. H. Freeze, E. Morava, D. J. Lefeber, T. Marquardt

Research output: Contribution to journalArticle

121 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)533-542
Number of pages10
JournalNew England Journal of Medicine
Volume370
Issue number6
DOIs
StatePublished - 2014

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Galactose
Glycosylation
Phosphoglucomutase
Phenotype
Congenital Disorders of Glycosylation
Dietary Supplements
Polysaccharides
Fibroblasts
Uvula
Glycogen Storage Disease
Exome
Malignant Hyperthermia
Mutation
Hypogonadism
Dilated Cardiomyopathy
Muscular Diseases
Enzymes
Transferrin
Heart Arrest
Cell Extracts

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Tegtmeyer, L. C., Rust, S., Van Scherpenzeel, M., Ng, B. G., Losfeld, M. E., Timal, S., ... Marquardt, T. (2014). Multiple phenotypes in phosphoglucomutase 1 deficiency. New England Journal of Medicine, 370(6), 533-542. https://doi.org/10.1056/NEJMoa1206605

Multiple phenotypes in phosphoglucomutase 1 deficiency. / Tegtmeyer, L. C.; Rust, S.; Van Scherpenzeel, M.; Ng, B. G.; Losfeld, M. E.; Timal, S.; Raymond, K.; He, P.; Ichikawa, M.; Veltman, J.; Huijben, K.; Shin, Y. S.; Sharma, V.; Adamowicz, M.; Lammens, M.; Reunert, J.; Witten, A.; Schrapers, E.; Matthijs, G.; Jaeken, J.; Rymen, D.; Stojkovic, T.; Laforêt, P.; Petit, F.; Aumaître, O.; Czarnowska, E.; Piraud, M.; Podskarbi, T.; Stanley, C. A.; Matalon, Reuben; Burda, P.; Seyyedi, S.; Debus, V.; Socha, P.; Sykut-Cegielska, J.; Van Spronsen, F.; De Meirleir, L.; Vajro, P.; DeClue, T.; Ficicioglu, C.; Wada, Y.; Wevers, R. A.; Vanderschaeghe, D.; Callewaert, N.; Fingerhut, R.; Van Schaftingen, E.; Freeze, H. H.; Morava, E.; Lefeber, D. J.; Marquardt, T.

In: New England Journal of Medicine, Vol. 370, No. 6, 2014, p. 533-542.

Research output: Contribution to journalArticle

Tegtmeyer, LC, Rust, S, Van Scherpenzeel, M, Ng, BG, Losfeld, ME, Timal, S, Raymond, K, He, P, Ichikawa, M, Veltman, J, Huijben, K, Shin, YS, Sharma, V, Adamowicz, M, Lammens, M, Reunert, J, Witten, A, Schrapers, E, Matthijs, G, Jaeken, J, Rymen, D, Stojkovic, T, Laforêt, P, Petit, F, Aumaître, O, Czarnowska, E, Piraud, M, Podskarbi, T, Stanley, CA, Matalon, R, Burda, P, Seyyedi, S, Debus, V, Socha, P, Sykut-Cegielska, J, Van Spronsen, F, De Meirleir, L, Vajro, P, DeClue, T, Ficicioglu, C, Wada, Y, Wevers, RA, Vanderschaeghe, D, Callewaert, N, Fingerhut, R, Van Schaftingen, E, Freeze, HH, Morava, E, Lefeber, DJ & Marquardt, T 2014, 'Multiple phenotypes in phosphoglucomutase 1 deficiency', New England Journal of Medicine, vol. 370, no. 6, pp. 533-542. https://doi.org/10.1056/NEJMoa1206605
Tegtmeyer LC, Rust S, Van Scherpenzeel M, Ng BG, Losfeld ME, Timal S et al. Multiple phenotypes in phosphoglucomutase 1 deficiency. New England Journal of Medicine. 2014;370(6):533-542. https://doi.org/10.1056/NEJMoa1206605
Tegtmeyer, L. C. ; Rust, S. ; Van Scherpenzeel, M. ; Ng, B. G. ; Losfeld, M. E. ; Timal, S. ; Raymond, K. ; He, P. ; Ichikawa, M. ; Veltman, J. ; Huijben, K. ; Shin, Y. S. ; Sharma, V. ; Adamowicz, M. ; Lammens, M. ; Reunert, J. ; Witten, A. ; Schrapers, E. ; Matthijs, G. ; Jaeken, J. ; Rymen, D. ; Stojkovic, T. ; Laforêt, P. ; Petit, F. ; Aumaître, O. ; Czarnowska, E. ; Piraud, M. ; Podskarbi, T. ; Stanley, C. A. ; Matalon, Reuben ; Burda, P. ; Seyyedi, S. ; Debus, V. ; Socha, P. ; Sykut-Cegielska, J. ; Van Spronsen, F. ; De Meirleir, L. ; Vajro, P. ; DeClue, T. ; Ficicioglu, C. ; Wada, Y. ; Wevers, R. A. ; Vanderschaeghe, D. ; Callewaert, N. ; Fingerhut, R. ; Van Schaftingen, E. ; Freeze, H. H. ; Morava, E. ; Lefeber, D. J. ; Marquardt, T. / Multiple phenotypes in phosphoglucomutase 1 deficiency. In: New England Journal of Medicine. 2014 ; Vol. 370, No. 6. pp. 533-542.
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title = "Multiple phenotypes in phosphoglucomutase 1 deficiency",
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.",
author = "Tegtmeyer, {L. C.} and S. Rust and {Van Scherpenzeel}, M. and Ng, {B. G.} and Losfeld, {M. E.} and S. Timal and K. Raymond and P. He and M. Ichikawa and J. Veltman and K. Huijben and Shin, {Y. S.} and V. Sharma and M. Adamowicz and M. Lammens and J. Reunert and A. Witten and E. Schrapers and G. Matthijs and J. Jaeken and D. Rymen and T. Stojkovic and P. Lafor{\^e}t and F. Petit and O. Auma{\^i}tre and E. Czarnowska and M. Piraud and T. Podskarbi and Stanley, {C. A.} and Reuben Matalon and P. Burda and S. Seyyedi and V. Debus and P. Socha and J. Sykut-Cegielska and {Van Spronsen}, F. and {De Meirleir}, L. and P. Vajro and T. DeClue and C. Ficicioglu and Y. Wada and Wevers, {R. A.} and D. Vanderschaeghe and N. Callewaert and R. Fingerhut and {Van Schaftingen}, E. and Freeze, {H. H.} and E. Morava and Lefeber, {D. J.} and T. Marquardt",
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TY - JOUR

T1 - Multiple phenotypes in phosphoglucomutase 1 deficiency

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 - Laforêt, P.

AU - Petit, F.

AU - Aumaître, O.

AU - Czarnowska, E.

AU - Piraud, M.

AU - Podskarbi, T.

AU - Stanley, C. A.

AU - Matalon, Reuben

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, E.

AU - Lefeber, D. J.

AU - Marquardt, T.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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U2 - 10.1056/NEJMoa1206605

DO - 10.1056/NEJMoa1206605

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JF - New England Journal of Medicine

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