MOGS-CDG: quantitative analysis of the diagnostic Glc 3 Man tetrasaccharide and clinical spectrum of six new cases.

Congenital disorders of glycosylation (CDG) are a clinically and biochemically heterogenous 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, 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 Glc 3 Man 7 GlcNAc 2 glycans 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 13 C 6 -2AA Glc 3 Man was used, while labeling efficiency was controlled by use of 12 C 6 -2AA and 13 C 6 - 2AA labeled laminaritetraose. Recovery, linearity, intra- inter coefficients of variability (CV %) of these labeled compounds were determined. Furthermore Glc 3 Man was specifically identified by retention time matching against authentic MOGS-CDG urine (factor accumulation) and Pompe urine. Glc 3 Man was increased in all six analyzed cases, ranging from 34,1- 618,0 μmol/mmol creatinine (reference <5 μmol). In short, MOGS-CDG has a broad manifestation of symptoms but can be diagnosed and more importantly quantified with the use of a targeted method for the urinary excretion of the Glc 3 Man biomarker. This article is protected by copyright. All rights reserved.