Jos Jansen

Chapter 1 14 β -Galactoside α 2,6-Sialyltransferase ( ST6GAL1 ) leading to hyposialylation and a type I CDG pattern.(31, 32) Hepatocellular carcinoma (HCC) has been associated with increased fucosylation in multiple publications.(33) Most notably, the increase in activity of α 1-6-Fucosyl transferase ( FUT8 ) results in hyperfucosylation of several proteins.(34) Of these proteins, α -fetoprotein (AFP) is used in diagnostics of HCC. Fucosylated AFP can better distinguish between HCC and non-HCC liver disease than non-fucosylated AFP.(35, 36) Congenital metabolic liver diseases As mentioned before, except for MPI-CDG, there are no CDG that present with isolated liver disease. Congenital metabolic liver diseases are a diverse group of diseases accounting for 6% of all liver transplantations in Europe in 2018.(37) This group is characterized by an autosomal dominant or recessive inherited pathogenic variant in a gene that codes for a hepatic enzyme. This can lead to an enzyme deficiency which leads to (1) structural liver disease with cirrhosis and ultimately liver related morbidity necessitating liver transplantation or (2) can cause injury to other organ systems. The most well-known metabolic liver diseases that cause structural liver damage are alpha 1 antitrypsin deficiency, hereditary hemochromatosis and Wilson disease. In these three diseases, hepatic injury is the result of accumulation of respectively polymerized alpha-1 antitrypsin, iron or copper.(38-40) Themainstay of treatment is lowering hepatic concentrations of these substances. Lesser prevalent diseases that cause hepatic injury are the intrahepatic cholestasis syndromes which are caused by defective intrahepatic bilirubin transport.(41) Metabolic liver diseases that additionally present with multisystemic disease symptoms can be attributed to defective metabolic pathways such as the urea cycle, glycogen storage, lipid metabolism, amino acid metabolism and carbohydrate metabolism. Liver transplantation is able to revert the liver phenotype in these patients in some cases.(42) As described in this thesis, the discovery of a CDG subgroup with a liver-dominant phenotype due to defects in assembly factors of the Vacuolar ATPase (V-ATPase) adds CDG to the list of congenital metabolic liver disease.