Jos Jansen

92 Chapter 4 homeostasis and a phenotype that contains elements of NAFLD and Wilson disease (Figure 1). Non-hepatic symptoms such as hypercholesterolemia (for all defects), neurodegenerative symptoms (CCDC115 and ATP6AP1 deficiency) and hypogammaglobulinemia (ATP6AP1 deficiency) may also be present (Table 2). Figure 1. Hepatic symptoms of V-ATPase assembly factor deficiencies A summary of hepatic symptoms to expect in patients with V-ATPase assembly factor deficiencies. On gross examination, the liver may be enlarged with signs of NAFLD. Biochemically, elevated aminotransferases and alkaline phosphatase and low ceruloplasmin are seen in plasma. Liver biopsy shows steatosis and copper accumulation. Structurally, dilation of the ER and the Golgi apparatus are present. Clinical spectrum Four patients, three adolescents and one adult, belonging to three families with a TMEM199 deficiency have been reported.(27) Table2 provides an overview of the different genotypes found to date. Two brothers were diagnosed with mildly elevated aminotransferases during routine check-up at adolescence. An adult male was diagnosed with unexplained elevation of aminotransferases and alkaline phosphatase (AP) for 21 years prior to discovery of abnormal Golgi glycosylation.(30) The fourth patient was diagnosed at the age of three months with benign idiopathic hypotonia. At the age of six years her aminotransferases were elevated and at the age of 13 abnormal Golgi glycosylation was detected. All patients presented with similar symptoms: mildly elevated aminotransferases ( < 5x upper limit of normal), elevated AP, and hepatic steatosis, clinically resembling NAFLD. Serum levels of ceruloplasmin were below 20 mg/dl, consistent with Wilson disease. Hepatic dry copper weight of one patient was 90 µg/g (normal < 40µg/g, for Wilson disease > 250 µg/g). Cholesterol (range 182 – 337 mg/dl) and low-density lipoprotein- cholesterol (range 111 -277 mg/dl) were