The congenital disorders of glycosylation: A multifaceted group of syndromes

Abstract

Summary:The congenital disorders of glycosylation (CDG) are a rapidly expanding group of metabolic syndromes with a wide symptomatology and severity. They all stem from deficient N-glycosylation of proteins. To date the group contains 18 different subtypes: 12 of Type I (disrupted synthesis of the lipid-linked oligosaccharide precursor) and 6 of Type II (malfunctioning trimming/processing of the protein-bound oligosaccharide). Main features of CDG involve psychomotor retardation; ataxia; seizures; retinopathy; liver fibrosis; coagulopathies; failure to thrive; dysmorphic features, including inverted nipples and subcutaneous fat pads; and strabismus. No treatment currently is available for the vast majority of these syndromes (CDG-Ib and CDG-IIc are exceptions), even though attempts to synthesize drugs for the most common subtype, CDG-Ia, have been made. In this review we will discuss the individual syndromes, with focus on their neuronal involvement, available and possible treatments, and future directions.

Serum transferrin carrying the xeno‐tetrasaccharide NeuAc‐Gal‐GlcNAc2 is a biomarker of ALG1‐CDG

“…Screening for serum TF underglycosylation is often the initial step in the metabolic investigation when deficient N-glycosylation is suspected (Eklund and Freeze 2006). This is often done by IEF, which is a stable and reliable method.…”

Severe, fatal multisystem manifestations in a patient with dolichol kinase-congenital disorder of glycosylation

“…N-linked CDG was suspected when ESI-MS of transferrin (Mayo Clinic, Rochester, MN) demonstrated elevated mono-oligosaccharide:di-oligosaccharide transferrin ratio of 0.707 (reference range < 0.100) and a-oligosaccharide:di-oligosaccharide transferrin ratio of 0.216 (reference range < 0.050). These ratios are indicative of Type I CDG, resulting in impaired synthesis or transfer of the LLO precursor that subsequently generates proteins with unoccupied glycosylation sites [2]. This is in comparison to Type II CDGs, which are caused by impaired processing, such as trimming and remodeling, of the protein-bound oligosaccharide, creating proteins that have fully occupied glycosylation sites but with abnormal glycans [2].…”

“…These ratios are indicative of Type I CDG, resulting in impaired synthesis or transfer of the LLO precursor that subsequently generates proteins with unoccupied glycosylation sites [2]. This is in comparison to Type II CDGs, which are caused by impaired processing, such as trimming and remodeling, of the protein-bound oligosaccharide, creating proteins that have fully occupied glycosylation sites but with abnormal glycans [2]. …”

“…N-linked glycosylation involves transfer of pre-assembled oligosaccharides from dolichol-pyrophosphate to an asparagine residue of a protein in the endoplasmic reticulum [1]. Isoelectric focusing (IEF), electrospray ionization mass spectrometry (ESI-MS), high performance liquid chromatography (HPLC), and capillary electrophoresis (CE) are used to search for patterns of underglycosylated serum transferrin seen in N-linked CDGs [2]. Because glycosylation is a fundamental process essential to protein and lipid function, CDGs have pleiotropic effects that often have severe or fatal manifestations in affected individuals.…”

Comparison between high performance liquid chromatography and capillary zone electrophoresis for the diagnosis of congenital disorders of glycosylation

“…The clinical spectrum is highly heterogeneous, with different levels of severity [2]. Patients may present a wide spectrum of clinical features that often imply multi-organ involvement [3,4].…”