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Adult presentation of MOGS-CDG: Expanding the Clinical Spectrum

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
MOGS-CDG (OMIM#606056) is a congenital disorder of glycosylation caused by the loss of function in the mannosyl-oligosaccharide glucosidase (Glucosidase I), encoded by the Gene MOGS. Glucosidase I removes non-reducing end alpha-1,2-linked glucose residues from Glc3Man9 once transferred from the dolichol donor to proteins in the endoplasmic reticulum (ER). MOGS-CDG presents with recurrent infections, dysmorphic features, cardiovascular structural abnormalities, severe global development delay, and hypogammaglobulinemia. Traditionally, biochemical diagnosis involves abnormal serum carbohydrate-deficient transferrin with a CDG type II pattern, a urine oligosaccharides analysis with an elevation of the Hexose tetrasaccharide (Hex4), which can be seen with patients Pompe, and N-Glycan analysis shows an elevation Glu3Man7GlcNAc2.

Case Presentation
This study describes a 40-year-old male presenting with multiple medical complications, including hypogammaglobulinemia without severe infections, gout with polyarticular pain, and type II diabetes mellitus with obesity. The patient also has dyslexia and a speech impediment, but no significant dysmorphic features. Differential diagnosis considered both primary and secondary causes of hypogammaglobulinemia, such as late-onset common variable immunodeficiency and factors like recurrent infections and metabolic diseases. Genetic testing revealed two variants in the MOGS gene, one likely pathogenic and the other of unknown significance. Serum carbohydrate-deficient transferrin analysis was normal, but plasma N-Glycan analysis indicated increased levels of Glc3Man7GlcNAc2 and Glc3Man8, suggesting MOGS-CDG (Congenital Disorder of Glycosylation, Type IIb).

Diagnostic Workup
Further testing using Liquid Chromatography High Resolutions Accurate Mass Spectrometry (LC-HRAM) confirmed the diagnosis by identifying specific N-glycan structures, including Glc3Man7-8 in IgG and an increased Glc3Man7 in a triple-depleted fraction (IgG, transferrin, albumin removed). Notably, the N-glycan profile in the patient's transferrin remained normal. MOGS-CDG results from the loss of function of mannosyl-oligosaccharide glucosidase (glucosidase I), an enzyme critical for glycoprotein quality control in the endoplasmic reticulum.

Conclusion
This unique presentation expands the clinical spectrum of MOGS-CDG, highlighting the importance of considering this diagnosis in adults with persistent hypogammaglobulinemia. The study underscores the sensitivity of semi-quantitative plasma N-glycan analysis in screening for MOGS-CDG, particularly when followed by IgG N-glycan profiling. This approach can enhance the detection of MOGS-CDG in patients with unexplained hypogammaglobulinemia, offering a path to accurate diagnosis and appropriate management.

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