Carbohydrate is closely related to many diseases. The first CDG patients with defective N-glycosylation were first described and characterized in 1980 by Jaeken et al. Currently, more than 45 types of CDG have been identified. It is a rapidly growing group of genetically and clinically heterogeneous disorders caused by defects of various steps in the glycan synthesis and processing pathway on asparagine (Asn)-linked glycoproteins. Although very rare, CDG is the fastest-growing group of the 3,000 known monogenic disorders. Most known CDG is genetically autosomal recessive, but there is also autosomal dominant (e.g., EXT1/EXT2-CDG) and X-linked forms (e.g., MGAT1-CDG). CDG often presents with a multisystem presentation and common symptoms are psychomotor retardation, developmental delay, coagulopathy, dysmorphic features, hypotonia, neurologic abnormalities, seizures, stroke-like seizures, and liver disease. Some individuals with CDG may also develop eye, skin, and heart problems. In conclusion, the phenotype range of CDG is very wide, ranging from severe to mild disease, from multisystem disease to single organ disease.
Traditional CDG classification is based on the pattern of transferrin subtype analysis. CDG is divided into type I (CDG-I) and type II (CDG-II). CDG-I is associated with dolichol (Dol)-linked glycans assembly and transfer defects localizing to the cytoplasm or endoplasmic reticulum (ER). CDG-II is attributed to a breakdown in the processing/assembly of protein-bound oligosaccharides in the Golgi apparatus. With the advent of widespread molecular diagnostics, most researchers use new nomenclature based on the names of the genes affected (e.g., CDG-Ia = PMM2-CDG). According to the new classification, CDG is divided into 4 categories of defects: defects of protein N-glycosylation, defects of protein O-glycosylation, defects of glycosphingolipid and glycosylphosphatidylinositol (GPI)-anchored glycosylation, and defects of multiple glycosylation and other pathways.
Sixteen protein N-glycosylation defects have been detected so far. These disorders are mainly divided into disorders of N-linked monosaccharide synthesis and interconversion and disorders of N-linked glycosylation.
These synthesis defects have been described including O-mannose (O-Man), O-N-acetylgalactosamine (O-GalNAc), O-N-acetylglucosamine (O-GlcNAc), O-glucose (O-Glc), O-fucose (O-Fuc), and O-xylose (O-Xyl).
The disorders are caused by the defects of mannosyltransferase in the GPI anchor biosynthesis pathway and the sialyltransferase in the ganglioside biosynthesis, respectively.
Due to the diversity of symptoms, the diagnosis of CDG is demanding. Laboratory analysis is very helpful in the diagnosis of CDG, such as glycan analysis, measurement of enzyme activity and metabolites, classical biochemical analysis, and molecular testing.
Almost all CDGs are associated with changes in glycosylation, so glycan analysis is the most promising method for screening CDGs. Isoelectric focusing (IEF) of transferrin is the simplest and most widely used CDG screening method for defects in N-glycan and O-glycan synthesis. However, this method is laborious, time-consuming, and not suitable for automation or precise quantification. In recent years, High-Performance Liquid Chromatography (HPLC), Mass Spectrometry (MS), and capillary zone electrophoresis (CZE) have been used to detect abnormal glycosylation patterns in CDG.
CDG is abnormally glycosylated due to insufficient or absent enzyme or transporter activity. Therefore, CDG is judged by measuring enzyme activity and metabolites. But this method is more difficult. Phosphomannose mutase 2 (PMM2) should be the enzyme of choice in CDG screening.
The study found that CDG-Ia is often accompanied by low plasma cholesterol concentration and cholinesterase activity with proteinuria. CDG-II is characterized by elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. Therefore, standard biochemical testing is helpful for the confirmation of specific CDGs.
CDG is associated with mutations in specific genes. Therefore, genomic mutations are identified by real-time polymerase chain reaction (PCR), DNA sequencing, single-strand conformation polymorphism analysis (SSCP), etc. In addition, this method is also used for the screening of mutation carriers in the population.
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