Jos Jansen

74 Chapter 3 During their last visit at the ages of 23 and 15 years, respectively, ALT and AST were within the normal range, but ALP was still slightly elevated. Lipid levels of individual F1-II2 had normalized, but for individual F1-II3, hypercholesterolemia persisted. Ceruloplasmin levels remained low for both individuals. Individual F2-II2 is a 41-year-old male with a clinical history of unexplained elevation of ATs and ALP. His clinical presentation has been described before.20 During routine pre-operative investigations for inguinal hernia surgery at the age of 11, incidentally, elevated ATs and ALP were found (ALT 190 U/l, AST 153 U/l, and ALP 718 U/l). At age 31, after 21 years of unexplained elevated ATs and ALP, a liver biopsy showed steatosis and minimal fibrosis with a hepatic dry copper weight of 90 mg/g (normal range, < 40 mg/g; for WD, > 250 mg/g). Serum ceruloplasmin was decreased (8.8 mg/dl) and urinary copper levels were normal. Kayser-Fleischer rings were absent. Based on these parameters, WD was discarded as a diagnosis. Additionally, hypercholesterolemia (204–337 mg/ dl) and elevated LDL-C (182–226 mg/dl) were present. Over the course of years, ATs regressed to normal (ALT 46–159 U/l, AST 40–110 U/l), but high ALP persisted (365–557 U/l). Metabolic screening showed a type 2 CDG pattern. Individual F3-II1 is a 23-year-old female born to Greek parents originating from the same small town. Her neonatal period was unremarkable. She was first seen by a clinician at the age of three months with hypotonia, which persisted during the following years. At the age of one year old, the diagnosis of benign infantile hypotonia was made. During early childhood, she also suffered from psychomotor disability. Brain MRI at the ages of four years and eleven years was normal. Due to attention deficit, carbamazepine was started at the age of six years but was discontinued after two years due to elevation of her liver enzymes, thought to be drug induced. Over the course of years, ATs and ALP remained elevated (ALT 36–172 U/l, AST 31–119 U/l, ALP 132–1,528 U/l) with low-normal ceruloplasmin (17–24 mg/dl). The lipid spectrum was normal until the age of five years, but cholesterol (231–257 mg/dl) and LDL-C (161–171 mg/ dl) increased when she got older. At the age of 13 years, metabolic screening revealed abnormal N- and O-glycosylation, in agreement with a diagnosis of type 2 CDG. Subunit analysis of the COG complex failed to detect mutations. Unfortunately, she was lost for follow-up until 2014. In 2014 she was doing well and her ALT, AST, and ALP were only slightly elevated (58 U/l, 52 U/l, and 132 U/l). Serum ceruloplasmin was low (18 mg/dl) and hypercholesterolemia persisted.