Mannosyl‐oligosaccharide glucosidase – congenital disorder of glycosylation: A patient with novel variants

Abstract

Key words congenital disorder of glycosylation, MOGS, whole exome sequencing. Congenital disorders of glycosylation (CDGs) are caused by deficient protein and lipid glycosylation. 1 Most CDGs are multisystem disorders. Mannosyl-oligosaccharide glucosidase congenital disorder of glycosylation (MOGS-CDG) is caused by recessive mutations in the mannosyl-oligosaccharide glucosidase I gene. Only six patients (from four families) have a d b c Fig. 1 (a) Clinical picture of the patient. (b) Echocardiogram of our patient revealed marked decrease in cardiac function. (c) Brain MRI scan, sagittal T1-weighted sequence displaying partial agenesis of the corpus callosum. (arrow) (d) Electropherogram shows novel compound heterozygous mutations in MOGS. Patient had compound heterozygous mutations: c.1483C>T nonsense mutation from the father and c.2255G>A missense mutation from the mother. (red arrows)

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

“…Seven individuals had a developmental and epileptic encephalopathy (DEE) characterised by frequent epileptiform activity with developmental regression or plateauing 28. EEG demonstrated typical DEE findings such as suppression-burst (P3 and P12), hypsarrhythmia (P6) and frequent multifocal epileptiform discharges as previously described 5 9–11. Seizure onset occured early, with seven probands having neonatal onset5 9–11 (online supplemental table S1).…”

“…Bi-allelic pathogenic variants in MOGS underlie MOGS-CDG, previously known as CDG-IIb (OMIM;606056), presenting with systemic manifestations and variable severity 5–11. Recently, there has been an increasing utilisation of next-generation sequencing for clinical application, but there is also a corresponding increase in the number of variants of unknown significance (VUS) that could not readily be subjected for functional validation, posing a challenge to clinicians in determining a precise diagnosis.…”

“…Thus, it is important to define molecular and biochemical tools that can solidify a diagnosis. While the majority of CDGs can be identified through carbohydrate deficient transferrin (CDT) testing in blood, some CDGs, including MOGS-CDG, will not be reliably detected using this methodology 5 9 11 12…”

Congenital disorders of glycosylation type IIb with MOGS mutations cause early infantile epileptic encephalopathy, dysmorphic features, and hepatic dysfunction

“…Based on our findings and those previously reported in eight patients, we defined a recognizable phenotype in CDG-IIb that comprised neurological symptoms including intractable seizures as early infantile epileptic encephalopathy, severe developmental delay, generalized hypotonia and microcephaly, hepatic dysfunction, and dysmorphic features, such as a broad nose, high arched palate, coarse face, arthrogryposis, overlapping fingers, hypertrichosis, and hypoplastic genitalia (Table 1) [5][6][7][8][9][10]. We noted that most patients had hearing impairment, potentially representing an additionally recognizable clinical feature of CDG-IIb.…”

“…Moreover, they described the pathological findings including cholangiofibrosis, myelin-like lamellar in the cytoplasm of hepatocytes, ballooning in neurons, and empty-looking vacuoles in the neuronal perikaryon; they detected tetrasaccharides in the urine specimen as a degraded product of unprocessed N-glycans [5]. Recently, a total of 8 cases of CDG-IIb with MOGS mutations have been reported (Table 1) [6][7][8][9][10]. Isoelectric focusing of transferrin (IEF-T) was performed in four patients, and three of four patients had a normal IEF-T profile.…”