Jos Jansen

6 139 Discussion and conclusion proven, a general defect of mislocalization or functioning of copper homeostasis proteins could produce the same phenotype. The V-ATPase assembly factors could possibly alter the pH of the TGN thereby influencing the function of ATP7B. The copper binding region of ATP7B is very sensitive for pH fluctuations.(26, 27) Although TGN pH for the V-ATPase assembly factors have yet to be determined, VMA21 mutations lead to an increase in lysosomal pH. Lysosomal acid lipase deficiency Patients with Lysosomal Acid Lipase (LAL) deficiency due to a defect in LIPA present with variable degrees of hepatomegaly, dyslipidaemia and liver cell damage. Its prevalence is estimated at 1 to 175.000.(28) Liver damage may vary from slight elevation of aminotransferases to fibrosis and progression to cirrhosis.(29) There is a distinction between severe, infantile-onset LAL-D (Wolman disease; MIM 278000) and the less severe form that usually presents in childhood or even adulthood (Cholesterol Ester Storage Disease (CESD); MIM 278000). Patients with Wolman disease usually decease before the age of 1 year, unless they are successfully treated with stem cell transplantation. CESD patients experience morbidity due to atherosclerosis, progressive liver disease, and/or malabsorption. LAL exhibits an important role in cholesterol and triglyceride homeostasis. In healthy individuals, LAL is located in lysosomes and hydrolyses cholesteryl esters and triglycerides to free cholesterol and fatty acids respectively. The cholesteryl esters and TGs are derived from endocytosed LDL particles. When lysosomal TG levels are low, activity of sterol regulatory element-binding proteins (SREBPs) is increased, leading to upregulation of HMG-CoA reductase. (30) Loss-of-function mutations in LAL-deficiency cause cholesteryl esters and triglycerides accumulation in the lysosome. In reaction to this, under normal levels of triglycerides, the SREBP pathway is activated. Consequently, endogenous cholesterol production is elevated resulting in increased levels of LDL and VLDL.(30) Niemann-Pick C CCDC115- and TMEM199 deficiency are hepatically characterized by steatosis and, especially CCDC115 deficiency, hepatomegaly. CCDC115 deficient patients phenotypically resemble lysosomal storage diseases such as Niemann-Pick