Jos Jansen

140 Chapter 6 disease type C (NPC, MIM257220). Although characterized as a lysosomal storage disease , in essence, NPC is a cholesterol-trafficking-disease caused by autosomal recessive mutations in NPC1 or NPC2 . Prevalence is estimated at 1:150.000.(31) Deficiency in either two leads to accumulation of unesterified cholesterol due to ineffective transportation out of the lysosomes. Secondarily, this imbalance in lysosomal lipids results in accumulation of lipids such as sphingomyelin and glucosylceramide.(32) Although NPC has a very heterogeneous presentation, the perinatal and early infantile period are often characterized by prolonged cholestatic icterus and regressing hepatosplenomegaly.(33) Interestingly, a subset of NPC patients develop an acute form of cholestatic jaundice with liver failure, similar to three out of eight CCDC115 deficient patients.(34) The mechanism behind cholesterol accumulation is incompletely understood. It is very likely that NPC1 and NPC2 act cooperatively; cytosolic NPC2 binds free cholesterol and presents it to NPC1. NPC1 then, by still unknown mechanism, transports cholesterol out of the lysosome. This process is dependent on functional vimentin, as NPC1-deficient cells have a hypophosphorylated form of vimentin with accumulation of Rab9.(35) The role of vimentin in lipid processing has long been known, as vimentin-deficient cells have abnormal lipid trafficking. (36) This is further highlighted by Genome wide associations studies (GWAS) identificationof thevimentin-containing loci associatedwithhigh total cholesterol levels.(37) In conclusion, although the considerable overlap in phenotype with CCDC115 deficient patients, a direct link between Golgi homeostasis defects and NPC1 deficiency is not yet recognized. 3. Can screening in a pre-selected patient group identify more patients with hepatic injury due to congenital glycosylation disorders? In chapter 5 we hypothesized that the a priori chance of identifying a CDG, and especially the V-ATPase assembly factor deficient CDG, would be increased in a cohort enriched with liver disease. This triggered us to develop a workflow for screening of a cohort consisting of patients with chronic liver disease and liver transplant recipients. In this study of > 1000 samples we failed to find a CDG with our workflow. We believe that the main reason for failure is the low prevalence of CDG and even more the subgroup V-ATPase assembly factor deficiencies. As we already described this in chapter 5, we will explore additional explanation in this section.