Jos Jansen

4 93 NAFLD Phenotype in Patients With V-ATPase Proton Pump Assembly Defects elevated. Liver biopsy showed mild steatosis and minimal fibrosis.(4) On follow- up aminotransferase levels were reduced but AP and cholesterol remained elevated and ceruloplasmin remained low. Table 2. Genotype overview of V-ATPase assembly factor deficiencies Gene sym- bol (Gene ID) Approved gene name (MIM) Locus Disorder (MIM) Inheri- tance Known patho- genic mutati- ons Protein change TMEM199 (NM_152464.2) Trans- membrane protein 199 (616815) 17q11.2 TMEM199- CDG (616829) Auto- somal recessive c.20C > A p.Ala7Glu c.[40G > C];[376- 1G > A] p.[Al- a14Pro];[p.0?] c.92G > C p.Arg31Pro CCDC115 (NM_032357.3) Coiled-coil do- main-con- taining protein 115 (613734) 2q21.1 CCDC115- CDG (616828) Auto- somal recessive c.92T > C p.Leu31Ser c.31G > T p.Asp11Tyr c.[92T > C];[(?_-258)_ (*1245_?) del] p.[Leu31S- er];[p.0?] ATP6AP1 (NM_001183.5) H+ trans- porting, lysosomal, accessory protein 1 (300197) Xq28 AT- P6AP1-CDG (300972) X-linked recessive c.1284G > A p.Met428Ile c.431T > C p.Leu144Pro c.1036G > A p.Glu346Lys c.938A > G p.Tyr313Cys Parallel to discovery of TMEM199 mutations, CCDC115 mutations in eight patients from five families (Table 2) were also described.(29) All patients developed symptoms during early infancy. Clinical features of CCDC115 deficiency overlap with that of TMEM199 deficiency. All patients displayed liver involvement with increased aminotransferases and alkaline phosphatase, low ceruloplasmin, and hypercholesterolemia. CCDC115 deficient patients develop neonatal jaundice, major hepatosplenomegaly, and psychomotor disability within the first months after birth, resembling lysosomal storage diseases. Patients may have mild dysmorphic features, facilitating diagnosis at an early age. The outcome of liver biopsy analysis was highly variable, encompassing the whole NAFLD spectrum from steatosis to cirrhosis. In one patient hepatic copper was increased at 125 µg/g dry weight , an increase that is insufficient for the diagnosis of Wilson disease. Three out of eight patients developed severe liver injury. Two underwent liver transplantation and one developed multi-organ failure and transplantation was omitted.