Jos Jansen

1 Introduction to hepatic congenital glycosylation disorders 13 Congenital Disorders of Glycosylation CDG are first discovered by Dr. Jaeken in 1980.(20) CDG are a rare but quickly expanding group of monogenic diseases affecting glycosylation.(21) Since 1980, over 100 monogenic defects have been described affecting different aspects of glycosylation.(22) To date, all CDG are inherited in an autosomal recessive pattern. CDG are classified into two types based on the cellular location of the defective protein. Type 1 CDG affect the assembly of glycans in the ER, either by lowering the supply of substrates (e.g. PMM2-CDG) or by directly compromising enzyme function (e.g. ALG3-CDG). Type 2 CDG affect glycan modification in the Golgi. This can be caused by insufficient influx of sugars due to defects in transferases (e.g. B4GALT1-CDG) or by a defect that leads to an imbalance in Golgi homeostasis.(23) Examples of the latter are: the Conserved oligomeric Golgi (COG) complex defects, which cause mislocalization of glycosyltransferases due to incorrect trafficking between Golgi stacks, or TMEM165-CDG and ATP6V0A2- CDG which lead to abnormal pH and electrolyte imbalance.(24-26) An overview of different CDG and their place in the glycosylation pathway can be seen in Figure 1. The phenotype of CDG patients Classically, IEM can be characterized as multisystemic diseases and CDG are no exception to this rule. All body systems are associated with CDG symptoms with a notable exception for the pulmonary system.(27) Frequently dysmorphic features are present and these are accompanied by severe psychomotor disability and failure to thrive. Biochemical liver abnormalities are frequently seen in CDG but often not of primary concern for clinicians.(28) An exception is MPI-CDG, which presents predominantly with liver disease and protein-losing enteropathy.(29) On the other hand, abnormal glycosylation per se can be attributed to liver dysfunction. Liver disease and abnormal glycosylation The liver is the main organ responsible for protein synthesis and secretion, and an effect on protein glycosylation can be expected in case of liver disease. Multiple liver diseases are associated with abnormal glycosylation. (30) Here, I will highlight two of the frequent and well-studied liver diseases. The most well- known liver disease to cause abnormal glycosylation is alcoholic liver disease. In fact, the alcohol consumption test (CDT) is based on decreased activity of