We report a term infant presenting in early infancy with progressive developmental delay, feeding difficulties, recurrent seizures and failure to thrive. The infant initially exhibited symptoms from early neonatal age, including vomiting, lethargy and seizures, necessitating multiple hospitalisations. Progressive neurological deterioration, hepatomegaly, bilateral nephromegaly, hypothyroidism, gastro-oesophageal reflux disease and auditory neuropathy were noted. MRI showed cerebral atrophy and dilated ventricles. Extensive investigations ruled out infections, metabolic acidosis and structural brain malformations. Whole exome sequencing identified a homozygous missense mutation in the mannosyl-oligosaccharide glucosidase (MOGS) gene (c.2090T>C; p.Leu697Ser), previously reported in MOGS CDG (congenital disorder of glycosylation type IIb). A mannose-based diet led to partial improvement. This case highlights the importance of considering neurometabolic conditions such as CDG in infants with early-onset developmental and epileptic encephalopathy and multisystem involvement. Early diagnosis and supportive multidisciplinary care are vital for improving outcomes and guiding family counselling.

Mannosyl-oligosaccharide Glucosidase (MOGS) initiates glycan trimming by specifically cleaving α-1,2-linked glucose residues on glycoproteins. MOGS is a key enzyme for proper N-glycosylation, and its defects are associated with rare disease MOGS related congenital disorders of glycosylation (MOGS-CDG). Although MOGS has been identified from most of eukaryotic organisms, its existence in prokaryotic remains unclear. In this study, a prokaryotic MOGS (pMOGS) was identified from Elizabethkingia meningoseptica FMS-007. During the process, a functional complementation assay was established by examining the N-glycans profile of a CWH41 (MOGS homologous gene) knockout strain of Saccharomyces cerevisiae. Using the assay system, the function of human MOGS and its disease related mutants were tested. This study extended our understandings of MOGS and our ability to approach MOGS-CDG.

Mannosyl-oligosaccharide glucosidase - congenital disorder of glycosylation (MOGS-CDG) is determined by biallelic mutations in the mannosyl-oligosaccharide glucosidase (glucosidase I) gene. MOGS-CDG is a rare disorder affecting the processing of N-Glycans (CDG type II) and is characterized by prominent neurological involvement including hypotonia, developmental delay, seizures and movement disorders. To the best of our knowledge, 30 patients with MOGS-CDG have been published so far. We described a child who is compound heterozygous for two novel variants in the MOGS gene. He presented Early Infantile Developmental and Epileptic Encephalopathy (EI-DEE) in the absence of other specific systemic involvement and unrevealing first-line biochemical findings. In addition to the previously described features, the patient presented a Hirschprung disease, never reported before in individuals with MOGS-CDG.

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 Glc3 Man7 GlcNAc2 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 13 C6 -2AA Glc3 Man was used, while labeling efficiency was controlled by use of 12 C6 -2AA and 13 C6 -2AA labeled laminaritetraose. Recovery, linearity, intra- and interassay coefficients of variability of these labeled compounds were determined. Furthermore, Glc3 Man was specifically identified by retention time matching against authentic MOGS-CDG urine and compared with Pompe urine. Glc3 Man 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 Glc3 Man excretion.

Mannosyl-oligosaccharide glucosidase (MOGS) deficiency is an extremely rare type of congenital disorder of glycosylation (CDG), with only 12 reported cases. Its clinical, genetic, and glycomic features are still expanding. Our aim is to update the novel clinical and glycosylation features of 2 previously reported patients with MOGS-CDG. We collected comprehensive clinical information, and conducted the immunoglobulin G1 glycosylation assay using nano-electrospray ionization source quadruple time-of-flight mass spectrometry. Novel dysmorphic features included an enlarged tongue, forwardly rotated earlobes, a birth mark, overlapped toes, and abnormal fat distribution. Novel imaging findings included pericardial effusion, a deep interarytenoid groove, mild congenital subglottic stenosis, and laryngomalacia. Novel laboratory findings included peripheral leukocytosis with neutrophil predominance, elevated C-reactive protein and creatine kinase, dyslipidemia, coagulopathy, complement 3 and complement 4 deficiencies, decreased proportions of T lymphocytes and natural killer cells, and increased serum interleukin 6. Glycosylation studies showed a significant increase of hypermannosylated glycopeptides (Glc3Man7GlcNAc2/N2H10 and Man5GlcNAc2/N2H5) and hypersialylated glycopeptides. A compensatory glycosylation pathway leading to an increase in Man5GlcNAc2/N2H5 was indicated with the glycosylation profile. We confirmed abnormal glycomics in 1 patient, expanding the clinical and glycomic spectrum of MOGS-CDG. We also postulated a compensatory glycosylation pathway, leading to a possible serum biomarker for future diagnosis.