Abstract
Congenital disorders of glycosylation (CDG) are a clinically and biochemically heterogeneous subgroup of inherited metabolic disorders. Most CDG with abnormal N-glycosylation can be detected by transferrin screening, however, MOGS-CDG escapes this routine screening. Combined with the clinical heterogeneity of reported cases, diagnosing MOGS-CDG can be challenging. Here, we clinically characterize ten MOGS-CDG cases including six previously unreported individuals, showing a phenotype characterized by dysmorphic features, global developmental delay, muscular hypotonia, and seizures in all patients and in a minority vision problems and hypogammaglobulinemia. Glycomics confirmed accumulation of a Glc3Man7GlcNAc2 glycan in plasma. For quantification of the diagnostic Glcα1-3Glcα1-3Glcα1-2Man tetrasaccharide in urine, we developed and validated a liquid chromatography-mass spectrometry method of 2-aminobenzoic acid (2AA) labeled urinary glycans. As an internal standard, isotopically labeled 13C6-2AA Glc3Man was used, while labeling efficiency was controlled by use of 12C6-2AA and 13C6-2AA labeled laminaritetraose. Recovery, linearity, intra- and interassay coefficients of variability of these labeled compounds were determined. Furthermore, Glc3Man was specifically identified by retention time matching against authentic MOGS-CDG urine and compared with Pompe urine. Glc3Man was increased in all six analyzed cases, ranging from 34.1 to 618.0 μmol/mmol creatinine (reference <5 μmol). In short, MOGS-CDG has a broad manifestation of symptoms but can be diagnosed with the use of a quantitative method for analysis of urinary Glc3Man excretion.
| Original language | English |
|---|---|
| Pages (from-to) | 313-325 |
| Number of pages | 13 |
| Journal | Journal of Inherited Metabolic Disease |
| Volume | 46 |
| Issue number | 2 |
| Early online date | 18 Jan 2023 |
| DOIs | |
| Publication status | Published - 12 Mar 2023 |
Bibliographical note
Funding Information: Glycomic studies were supported by ZonMw Medium Investment Grant 40‐00506‐98‐9001 and EUROGLYCAN‐omics (ERARE18‐117) by ZonMw (90030376501), under the frame of E‐Rare‐3, the ERA‐Net for Research on Rare Diseases. The research conducted at the Murdoch Children's Research Institute was supported by the State Government of Victoria's Operational Infrastructure Support Program. The Chair in Genomic Medicine awarded to JC is generously supported by The Royal Children's Hospital Foundation. Katrin Õunap and Mari‐Anne Vals are supported by Eesti Teadusagentuur grant PRG471. The research conduction at Amsterdam UMC is supported by Stichting Metakids, NL. Several author(s) (DJL, CvK, SBW) of this publication are (affiliated) members of the European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN) ‐ Project ID No. 739543. The funding organizations had no role in the design or conduct of this research.Funding Information:
E‐Rare, Grant/Award Number: 90030376501; Estonian Research Council, Grant/Award Number: PRG471; ZonMW Medium Investment Grant, Grant/Award Number: 40‐00506‐98‐9001; State Government of Victoria's Operational Infrastructure Support Program; The Royal Children's Hospital Foundation; Stichting Metakids Funding information
Publisher Copyright: © 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.