Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation

Abstract

PurposeTo summarise the clinical, molecular and biochemical phenotype of mannosyl-oligosaccharide glucosidase-related congenital disorders of glycosylation (MOGS-CDG), which presents with variable clinical manifestations, and to analyse which clinical biochemical assay consistently supports diagnosis in individuals with bi-allelic variants inMOGS.MethodsPhenotypic characterisation was performed through an international and multicentre collaboration. Genetic testing was done by exome sequencing and targeted arrays. Biochemical assays on serum and urine were performed to delineate the biochemical signature of MOGS-CDG.ResultsClinical phenotyping revealed heterogeneity in MOGS-CDG, including neurological, immunological and skeletal phenotypes. Bi-allelic variants inMOGSwere identified in 12 individuals from 11 families. The severity in each organ system was variable, without definite genotype correlation. Urine oligosaccharide analysis was consistently abnormal for all affected probands, whereas other biochemical analyses such as serum transferrin analysis was not consistently abnormal.ConclusionThe clinical phenotype of MOGS-CDG includes multisystemic involvement with variable severity. Molecular analysis, combined with biochemical testing, is important for diagnosis. In MOGS-CDG, urine oligosaccharide analysis via matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry can be used as a reliable biochemical test for screening and confirmation of disease.

MOGS‐CDG: Quantitative analysis of the diagnostic Glc3Man tetrasaccharide and clinical spectrum of six new cases

“…Recently, Shimada et al reported an extensive clinical review of MOGS-CDG patients. 12 Most clinical features found in our novel cases are in line with those reported in that study and other previous studies. The core phenotype includes dysmorphic features, global developmental delay, hypotonia, and seizures.…”

“…This formula is also applied to labeling control L4. After these calculations, the concentration of 12 C 6 2AA-labeled T4 was corrected with the use of L4 via formula: Corrected concentration 12 C 6 2AA-labeled T4 (μmol/mmol creatinine) = calculated concentration 12 C 6 2AA-labeled T4 (μmol/mmol creatinine)/calculated concentration 12 C 6 2AA-labeled L4 (μmol/mmol creatinine) Â added 13 C 6 2AA-labeled IS L4 (μmol/mmol creatinine).…”

“…Analysis was performed by LC-MS/MS, using ZIC-HILIC chromatography. After optimization of collision energies, MRM transitions were selected for analysis of 12 After correction for labeling efficiency, quantification of the diagnostic T4 tetraglucoside in urine samples was achieved by using the 13 C 6 2AA-labeled T4 IS. Coefficient of variability (CV) was determined in urine samples with low, medium, and high secretion of T4 within 1 batch and several batches and showed to be <10% (Supplementary Table 6).…”

“…4 Thus far, 24 cases of MOGS-CDG have been described. 2,[5][6][7][8][9][10][11][12][13] The reported clinical features include facial dysmorphisms, neurologic symptoms (global developmental delay, muscular hypotonia, seizures), immune dysfunction related to hypogammaglobulinemia, hepatomegaly, and other less common features. Nevertheless, the phenotypic spectrum and natural history remain to be delineated, especially given the limited number of cases.…”

“…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-and interassay coefficients of variability of these labeled compounds were determined.…”