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

Abstract

Purpose: To 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 in MOGS.

Methods: Phenotypic 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.

Results: Clinical phenotyping revealed heterogeneity in MOGS-CDG, including neurological, immunological and skeletal phenotypes. Bi-allelic variants in MOGS were 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.

Conclusion: The 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.

Keywords: central nervous system diseases; diagnosis; glycomics; human genetics; sequence analysis, DNA.

Figure 1

A. Schematic presentation of MOGS and MOGS protein structure. MOGS consists of 4 exons, and the MOGS protein shows different functional domains. Previously reported variants are shown below the structure, and variants identified in this study are above the structure. Newly reported variants are in red. B. Dysmorphic features of probands with MOGS variants. Proband 1 (P1) at age 20 (a), proband 2 (P2) at age 15 (b and c), proband 3 (P3) at age 11 (d), proband 8 (P8) at age 4 (e and f) and proband 11 (P11) at 1.5 month of age (g). Both P1 and P2 had broad nasal tip and retrognathia (a and b). P2 had 2^nd and 3^rd toe syndactyly with overlapping toes (c). P3, P8 and P11 had broad nasal tip, smooth philtrum, downturned corner of mouth and retrognathia (d, e, f, g). C. Clinical summary for 12 probands with bi-allelic MOGS variants. Note all probands showed developmental delay, dysmorphic features, hypogammaglobulinemia. The denominator reflects the availability of clinical information. AST, aspartate aminotransferase.

Figure 2.. Radiographs of skeletal findings in individuals with MOGS-CDG.

A. Radiographs of hands of proband 1 (P1) at age 10 (1) and 20 (2), proband 2 (P2) at age 10, proband 3 (P3) at age 11 and proband 11 (P11) at 1.5 months of age. Note osteopenia in P1, P2 and P3, partial pseudo-epiphysial formation P1 (1) and shortened metacarpals (P11). B. Radiographs of upper extremities of P2 at age 10, P3 at age 11, P4 at 1 month of age (1 and 2) and P11 at 1.5 months of age, radiograph of thorax of P4 at 1 month (3). Note thin diaphysis and osteopenia in P2 and P3, bilateral ulnar deviation at the wrist in P4, and bell-shaped thorax. C. Radiographs of lower extremities of P1 at age 15, P2 at age 10, P3 at age 11, P4 at 1 month of age and P11 at 1.5 months of age. Note thin diaphysis in P1, P2 and P3 especially in the fibulas (P2), bowing femur (P1), metaphyseal flaring (P2, P3 and P11) and widening of the diaphysis with a permeative pattern, consistent with expansion of the intramedullary spaces (P4). D. Radiographs of pelvis in P3 at age 11, and P4 at age 1 month (1) and 19 months (2). Note protrusion acetabuli (P3) and deformity of femoral head and pelvis (P4). E. Radiographs of lateral lumbar spine in P1 at age 11, P4 at 1 month of age and P11 at 1.5 months of age. Note the Pars interarticularis defects at the L5 in P1 and elongated spine in P2.

Figure 3.. Urine oligosaccharide profile.

A. MALDI-TOF MS glycan profile in urine. Glycan profiles of urine oligosaccharide from control, P3 and P4. MALDI-TOF MS profile demonstrates a consistently larger than normal peak at 885 m/z (P3 and P4). B. MALDI-TOF/TOF analysis in urine oligosaccharide. Representative profile of urine oligosaccharides from MOG-CDG proband (P1). Fragmentation pattern of the compound was done by using MALDI TOF/TOF to fragment 885 m/z. The m/z of Y1, B2, Y2, B1 and Y3 fragments of Hexose 4 are: 259.1, 445.2, 463.2, 649.2, 667.2. Mannose is shown as green and glucose as blue. C. Urine oligosaccharide fluorescent labeling and HPLC. The fluorescence chromatograph of 2-aminobenzimide (2-AB) labeled reducing end monosaccharide. Standards are glucose (light blue), mannose (pink), and polyglucose (green). Urine oligosaccharides from a proband diagnosed with Pompe disease are in brown, and MOGS-CDG (P1) is in blue. Note the retention time of reducing end mono-saccharides from polyglucose, and urinary oligosaccharides of a known Pompe proband are consistent with that of the glucose standard, while the retention time of the reducing end mono-saccharide from our MOGS-CDG probands is the same as the mannose standard. Fluorescence (330 nm excitation; 420 nm emission) was used to detect the 2-AB derivatives. 2-AB, 2-aminobenzamide; TFA, trifluoroacetic acid. D. HPAEC-PAD component analysis of urine monosaccharides. Analysis shows chromatograms from normal control and proband with MOGS-CDG using Dionex ICS-3000 with a Carbpac PA-10 column. The eluent gradient was set to 2.5–125 mM sodium acetate over 100 minutes in 100 mM sodium hydroxide. The levels of both glucose and mannose are increased in the patient’s urine post TFA hydrolysis. The ratio of fluorescence intensity between Peak 4 (glucose) and Peak 5 (mannose) is close to 3.0. Small amounts of galactosamine (GalNH2), glucosamine (GlcNH2), and galactose (Gal), are seen as components of normal urinary oligosaccharides.