Journal of Inherited Metabolic Disease

, Volume 36, Issue 3, pp 535–542 | Cite as

A novel congenital disorder of glycosylation type without central nervous system involvement caused by mutations in the phosphoglucomutase 1 gene

  • Belén Pérez
  • Celia Medrano
  • Maria Jesus Ecay
  • Pedro Ruiz-Sala
  • Mercedes Martínez-Pardo
  • Magdalena Ugarte
  • Celia Pérez-CerdáEmail author
Original Article


Recent years have seen great advances in our knowledge of congenital disorders of glycosylation (CDG), a clinically and biochemically heterogeneous group of genetic diseases caused by defects in the synthesis (CDG-I) or processing (CDG-II) of glycans that form glycoconjugates. This paper reports a new subtype of non-neurological CDG involving the impaired cytoplasmic biosynthesis of nucleotide sugars needed for glycan biosynthesis. A patient presented with muscle fatigue, elevated creatine kinase, growth hormone deficiency, and first branchial arch syndrome. These findings, together with the abnormal type II plasma transferrin isoform profile detected, was compatible with a CDG. Functional testing and clinical analyses suggested a deficiency in the interconversion of glucose-1-phosphate and glucose-6-phosphate catalyzed by phosphoglucomutase (PGM1), a defect previously described as glycogenosis type XIV (GSDXIV, MIM 612934). PGM1 activity in patient-derived fibroblasts was significantly reduced, as was the quantity of immunoreactive PGM1 protein (Western blot assays). Mutation analysis of PGM1 and subsequent functional analysis investigating transient expression of PGM1 in immortalized patient fibroblasts, followed by ex vivo splicing assays using minigenes, allowed the characterization of two novel pathogenic mutations: c.871G>A (p.Gly291Arg) and c.1144 + 3A>T. The latter represents a severe splicing mutation leading to the out-of-frame skipping of exon 7 and the formation of a truncated protein (p.Arg343fs). MALDI mass spectra of permethylated protein N-glycans from the patient’s serum suggested a marked hypoglycosylation defect. The present findings confirm that, in addition to a rare muscular glycolytic defect, PGM1 deficiency causes a non-neurological disorder of glycosylation.


Growth Hormone Deficiency Nucleotide Sugar Phosphoglucomutase Supplemental Data Table Splice Assay 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was funded by grants from the Spanish Ministerio de Ciencia e Innovación (PI10/00455 to BP and PI11/01254 to CPC). An institutional grant from the Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa is gratefully acknowledged. Authors also thank Mª Teresa Alonso from Servicio Interdepartamental de Investigación (SIDI-UAM) for glycan analysis by MALDI-TOF-mass spectrometry.

Details of funding

The authors confirm independence from the sponsors, and the content of the article has not been influenced by the sponsors.

Conflict of interest


Supplementary material

10545_2012_9525_MOESM1_ESM.docx (48 kb)
ESM 1 (DOCX 47 kb)
10545_2012_9525_MOESM2_ESM.docx (15 kb)
ESM 2 (DOCX 15 kb)


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Copyright information

© SSIEM and Springer 2012

Authors and Affiliations

  • Belén Pérez
    • 1
  • Celia Medrano
    • 1
  • Maria Jesus Ecay
    • 1
  • Pedro Ruiz-Sala
    • 1
  • Mercedes Martínez-Pardo
    • 2
  • Magdalena Ugarte
    • 1
  • Celia Pérez-Cerdá
    • 1
    • 3
    Email author
  1. 1.Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular UAM-CSIC, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)IDIPaz, Universidad Autónoma MadridMadridSpain
  2. 2.Unidad de Metabolopatías, Servicio de Pediatría, Hospital Ramón y CajalMadridSpain
  3. 3.Centro de Diagnóstico de Enfermedades MolecularesUniversidad Autónoma MadridMadridSpain

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