Jos Jansen

88 Chapter 4 Abstract NAFLD is a common liver disease with a multifactorial etiology with hepatic steatosis as a signature lesion. Secondary causes for NAFLD are important to recognize because of their clear different clinical trajectory. In this review, we describe rare genetic variants in CCDC115 , TMEM199, and ATP6AP1 that can result in hepatic steatosis. These genes encode assembly factors of the vacuolar H+ ATPase proton pump and their deficiency results in abnormal Golgi homeostasis with subsequent abnormal protein glycosylation. Patients present with elevated aminotransferases and alkaline phosphatase and steatosis on liver biopsy. Hepatosplenomegaly is present in a subgroup and progression to cirrhosis with acute liver failure necessitating liver transplantation has been reported. The extra-hepatic phenotype includes dyslipidemia, muscular hypotonia, recurrent infections, and cognitive impairment. In light of these novel findings, V-ATPase assembly factor deficiencies should be recognized as a cause for secondary NAFLD and additionally provide valuable new insights in NAFLD disease mechanisms. We hypothesize a role for defective intracellular lipid metabolism via COPI and COPII vesicles to explain the hepatic phenotype.