Jos Jansen

2 35 CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation Results Clinical Phenotype All affected individuals (see pedigrees in Figure 1A and overview in Table 1) had a similar phenotype with storage-disease-like symptoms at a younger age. These included hepatosplenomegaly, hypotonia, elevated serum aminotransferases (ATs, composed of aspartate and alanine aminotransferases [AST, ALT]), and elevated serum alkaline pho sphatase (ALP). Additional symptoms included psychomotor disability (PMD), mild hypercholesterolemia, and low serum ceruloplasmin. Siblings F1-II1 (female, born in 2000) and F1-II2 (male, born in 2004) from family F1 were from Turkish ancestry and have been described previously.24 Their parents are first cousins. During our studies, a younger affected sister was born (individual F1-II4, female, born in 2012). Overall, their symptoms were dominated by PMD, hypotonia, and hepatosplenomegaly with elevated AT and ALP. Metabolic screening revealed a type 2 CDG profile. Individual F1-II1 was first seen at the age of nine years. Her neonatal period was unremarkable. At examination there was a generalized hypotonia and PMD. She showed mild dysmorphic features. Over the years her AT and ALP fluctuated but were always elevated (AST 130–158 U/l [normal range, 0–50 U/l], ALT 85–101 U/l [normal range, 0–50 U/l], and ALP 1,016 –1,193 U/l [normal range, < 360 U/l]). Isotype analysis showed that ALP was mostly bone derived, as seen in defects of glycosylphosphatidylinositol (GPI)-anchor biosynthesis. However, surface expression of GPI-anchored proteins CD59 and CD55 in EBV-transformed lymphoblasts did not confirm a GPI-anchor defect (data not shown). Additional biochemical analysis showed low serum ceruloplasmin (4 mg/dl [normal range, 15–60 mg/dl]), decreased coagulation factors, and elevated creatine kinase. Total cholesterol and low-density lipoprotein (LDL-C) were normal. Her brother, F1-II2, was also seen in 2009 at the age of five years. He shared the same phenotype as his sister but had additional dysmorphic features (long face, ptosis, blue sclera,and down-slanting palpebral fissures). In addition to generalized hypotonia, muscle atrophy was present. Biochemically, elevated AT and ALP (AST 96–436 U/l, ALT 140–995 U/l, and ALP 1,070–1,577 U/l), low ceruloplasmin (4 mg/dl), hypercholesterolemia (289 mg/dl [normal range, 120– 200 mg/dl]), and abnormal coagulation factors were seen over time.