Clinical Information

Glycosylation is the post-translational modification of proteins and lipids by the addition of glycans (sugars and sugar chains) in a complex stepwise fashion in the endoplasmic reticulum, Golgi apparatus, cytosol and sarcolemmal membrane. Congenital disorders of glycosylation (CDG) are a group of over 150 inherited metabolic disorders characterized by abnormal protein and lipid glycosylation. There are 2 main groups of CDG: type I, characterized by defects in the assembly or transfer of the dolichol-linked glycan in either the cytosol or endoplasmic reticulum (ER) and type II, involving processing defects of the glycan in the ER and Golgi apparatus. In addition, there are 2 main categories of glycosylation: N-glycosylation where N-linked glycans are attached to a protein backbone via an asparagine residue on the protein, and O-glycosylation where O-glycans are attached to the hydroxyl group of threonine or serine. Apolipoprotein CIII (Apo-CIII) isoforms, with a single core 1 mucin type O-glycosylate protein, is a complementary evaluation for the CDG type II profile. This analysis will evaluate mucin type O-glycosylation, a defect involving the Golgi apparatus, which is detected biochemically by the change in ratios of the 3 isoforms.

CDG typically present as multi-systemic disorders with a broad clinical spectrum including, but not limited to, developmental delay, hypotonia, with or without neurological abnormalities, abnormal magnetic resonance imaging findings, skin manifestations, and coagulopathy. There is considerable variation in the severity of this group of diseases ranging from a mild presentation in adults and children to severe multi-organ dysfunctions causing infant lethality. In some subtypes, phosphomannose isomerase-CDG (MPI-CDG or CDG-Ib) in particular, intelligence is not compromised. CDG should be suspected in all patients with neurological abnormalities including developmental delay and seizures, brain abnormalities such as cerebellar atrophy or hypoplasia as well as unexplained liver dysfunction. Abnormal subcutaneous fat distribution and chronic diarrhea each may or may not be present. The differential diagnosis of abnormal transferrin patterns also includes liver disease not related to CDG including galactosemia, hereditary fructose intolerance in acute crisis, and liver disease of unexplained etiology.

Transferrin and apolipoprotein CIII isoform analysis are the initial screening tests for CDG. The results of the transferrin and apolipoprotein CIII isoform analysis should be correlated with the clinical presentation to determine the most appropriate follow-up testing strategy including enzyme, molecular, and research-based testing. Enzymatic analysis for phosphomannomutase and phosphomannose isomerase in leukocytes (PMMIL / Phosphomannomutase and Phosphomannose Isomerase, Leukocytes) should be performed if either PMM2-CDG (CDG-Ia) or MPI-CDG (CDG-Ib) is suspected.

Other glycosylation pathways, in addition to N- and O-glycosylation, have been elucidated, in particular glycophosphatidylinositol (GPI)-anchored protein glycosylation disorders in which there is absent or decreased expression of all the GPI-linked antigens, and alpha-dystroglycanopathies caused by impaired synthesis of O-mannose glycans. Neither class of disorders are picked up by CDG analysis in serum but are typically diagnosed using molecular methods (CDGGP / Congenital Disorders of Glycosylation Gene Panel, Varies).