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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