Phosphoglucomutase 1 (PGM1) deficiency results in a mixed phenotype of a Glycogen Storage Disorder and a Congenital Disorder of Glycosylation (CDG). Screening for abnormal glycosylation has identified more than 40 patients, manifesting with a broad clinical and biochemical spectrum which complicates diagnosis. Together with the availability of D-galactose as dietary therapy, there is an urgent need for specific glycomarkers for early diagnosis and treatment monitoring. We performed glycomics profiling by high-resolution QTOF mass spectrometry in a series of 19 PGM1-CDG patients, covering a broad range of biochemical and clinical severity. Bioinformatics and statistical analysis were used to select glycomarkers for diagnostics and define glycan-indexes for treatment monitoring. Using 3 transferrin glycobiomarkers, all PGM1-CDG patients were diagnosed with 100% specificity and sensitivity. Total plasma glycoprofiling showed an increase in high mannose glycans and fucosylation, while global galactosylation and sialylation were severely decreased. For treatment monitoring, we defined 3 glycan-indexes, reflecting normal glycosylation, a lack of complete glycans (LOCGI) and of galactose residues (LOGI). These indexes showed improved glycosylation upon D-galactose treatment with a fast and near-normalization of the galactose index (LOGI) in 6 out of 8 patients and a slower normalization of the LOCGI in all patients. Total plasma glycoprofiling showed improvement of the global high mannose glycans, fucosylation, sialylation, and galactosylation status on D-galactose treatment. Our study indicates specific glycomarkers for diagnosis of mildly and severely affected PGM1-CDG patients, and to monitor the glycan-specific effects of D-galactose therapy.

Academic Centre on Rare Diseases University College Dublin Dublin Republic of Ireland

Biochemical Diseases Mater Children's Hospital South Brisbane Queensland Australia

Center for Child and Adolescent Medicine Kinderheilkunde 1 University of Heidelberg Heidelberg Germany

Department of Clinical Genomics CIM Mayo Clinic Rochester Minnesota

Department of Inborn Errors of Metabolism and Paediatrics Institute of Mother and Child Warsaw Poland

Department of Internal Medicine Radboud University Medical Center Nijmegen The Netherlands

Department of Neurology and Translational Metabolic Laboratory Donders Institute for Brain Cognition and Behavior Radboud University Medical Center Nijmegen The Netherlands

Department of Neurology Radboud University Medical Center Nijmegen The Netherlands

Department of Neurology University of Copenhagen Denmark

Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Prague Czech Republic

Institute of Clinical Biochemistry Faculty of Medicine University of Oslo and Department of Medical Biochemistry Oslo University Hospital Norway

Translational Metabolic Laboratory Radboud University Medical Center Nijmegen The Netherlands

University Hospital Muenster Muenster Germany

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Stojkovic T, Vissing J, Petit F, et al. Muscle glycogenosis due to phosphoglucomutase 1 deficiency. The New England journal of medicine. 2009; 361: 425–7. PubMed

Timal S, Hoischen A, Lehle L, et al. Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing. Human molecular genetics. 2012; 21: 4151–61. PubMed

Tegtmeyer LC, Rust S, van Scherpenzeel M, et al. Multiple phenotypes in phosphoglucomutase 1 deficiency. The New England journal of medicine. 2014; 370: 533–42. PubMed PMC

Morava E Galactose supplementation in phosphoglucomutase-1 deficiency; review and outlook for a novel treatable CDG. Molecular genetics and metabolism. 2014; 112: 275–9. PubMed PMC

Voermans NC, Preisler N, Madsen KL, et al. PGM1 deficiency: Substrate use during exercise and effect of treatment with galactose. Neuromuscular disorders : NMD. 2017; 27: 370–6. PubMed

Wong SY, Gadomski T, van Scherpenzeel M, et al. Oral D-galactose supplementation in PGM1-CDG. Genetics in medicine : official journal of the American College of Medical Genetics. 2017; 19: 1226–35. PubMed PMC

Ondruskova N, Honzik T, Vondrackova A, Tesarova M, Zeman J and Hansikova H. Glycogen storage disease-like phenotype with central nervous system involvement in a PGM1-CDG patient. Neuro endocrinology letters. 2014; 35: 137–41. PubMed

Jansen JC, Cirak S, van Scherpenzeel M, et al. CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation. American journal of human genetics. 2016; 98: 310–21. PubMed PMC

van Scherpenzeel M, Steenbergen G, Morava E, Wevers RA and Lefeber DJ. High-resolution mass spectrometry glycoprofiling of intact transferrin for diagnosis and subtype identification in the congenital disorders of glycosylation. Translational research : the journal of laboratory and clinical medicine. 2015; 166: 639–49.e1. PubMed

Kronewitter SR, de Leoz ML, Peacock KS, et al. Human serum processing and analysis methods for rapid and reproducible N-glycan mass profiling. Journal of proteome research. 2010; 9: 4952–9. PubMed PMC

Hua S, Williams CC, Dimapasoc LM, et al. Isomer-specific chromatographic profiling yields highly sensitive and specific potential N-glycan biomarkers for epithelial ovarian cancer. Journal of chromatography A. 2013; 1279: 58–67. PubMed PMC

Guillard M, Morava E, van Delft FL, et al. Plasma N-glycan profiling by mass spectrometry for congenital disorders of glycosylation type II. Clinical chemistry. 2011; 57: 593–602. PubMed

Xia B, Zhang W, Li X, et al. Serum N-glycan and O-glycan analysis by mass spectrometry for diagnosis of congenital disorders of glycosylation. Analytical biochemistry. 2013; 442: 178–85. PubMed

Callewaert N, Schollen E, Vanhecke A, Jaeken J, Matthijs G and Contreras R. Increased fucosylation and reduced branching of serum glycoprotein N-glycans in all known subtypes of congenital disorder of glycosylation I. Glycobiology. 2003; 13: 367–75. PubMed

Sturiale L, Barone R, Fiumara A, et al. Hypoglycosylation with increased fucosylation and branching of serum transferrin N-glycans in untreated galactosemia. Glycobiology. 2005; 15: 1268–76. PubMed

Hills AE, Patel A, Boyd P and James DC. Metabolic control of recombinant monoclonal antibody N-glycosylation in GS-NS0 cells. Biotechnology and bioengineering. 2001; 75: 239–51. PubMed

Pacis E, Yu M, Autsen J, Bayer R and Li F. Effects of cell culture conditions on antibody N-linked glycosylation--what affects high mannose 5 glycoform. Biotechnology and bioengineering. 2011; 108: 2348–58. PubMed

Chee Furng Wong D, Tin Kam Wong K, Tang Goh L, Kiat Heng C and Gek Sim Yap M. Impact of dynamic online fed-batch strategies on metabolism, productivity and N-glycosylation quality in CHO cell cultures. Biotechnology and bioengineering. 2005; 89: 164–77. PubMed

Slade PG, Caspary RG, Nargund S and Huang CJ. Mannose metabolism in recombinant CHO cells and its effect on IgG glycosylation. Biotechnology and bioengineering. 2016; 113: 1468–80. PubMed

Lauc G, Essafi A, Huffman JE, et al. Genomics meets glycomics-the first GWAS study of human N-Glycome identifies HNF1alpha as a master regulator of plasma protein fucosylation. PLoS genetics. 2010; 6: e1001256. PubMed PMC

Kim JH, Lee SH, Choi S, et al. Direct analysis of aberrant glycosylation on haptoglobin in patients with gastric cancer. Oncotarget. 2017; 8: 11094–104. PubMed PMC

International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management