Clinical and Biochemical Characteristics of Congenital Disorder of Glycosylation Type Ic, the First Recognized Endoplasmic Reticulum Defect in N-Glycan Synthesis S. Gru¨newald, MD,*² T. Imbach, MD,‡ K. Huijben,§ M. E. Rubio-Gozalbo, MD, i A. Verrips, MD, i J. B. C. de Klerk, MD,¶ H. Stroink, MD,¶ J. F. de Rijk-van Andel, MD,# J. L. K. Van Hove, MD, PhD,** U. Wendel, MD, PhD,* G. Matthijs, PhD,² T. Hennet, PhD,‡ J. Jaeken, MD, PhD,** and R. A. Wevers, PhD§ We report on 8 patients with a recently described novel subtype of congenital disorder of glycosylation type Ic (CDG-Ic). Their clinical presentation was mainly neurological with developmental retardation, muscular hypotonia, and epilepsy. Several symptoms commonly seen in CDG-Ia such as inverted nipples, abnormal fat distribution, and cerebellar hyp- oplasia were not observed. The clinical course is milder overall, with a better neurological outcome, than in CDG-Ia. The isoelectric focusing pattern of serum transferrin in CDG-Ia and CDG-Ic is indistinguishable. Interestingly, b-trace pro- tein in cerebrospinal fluid derived from immunoblot analysis of the brain showed a less pronounced hypoglycosylation pattern in CDG-Ic patients than in CDG-Ia patients. Analysis of lipid-linked oligosaccharides revealed an accumulation of Man 9 GlcNAc 2 intermediates due to dolichol pyrophosphate–Man 9 GlcNAc 2 a-1,3 glucosyltransferase deficiency. All patients were homozygous for an A333V mutation. Gru¨newald S, Imbach T, Huijben K, Rubio-Gozalbo ME, Verrips A, de Klerk JBC, Stroink H, de Rijk-van Andel JF, Van Hove JLK, Wendel U, Matthijs G, Hennet T, Jaeken J, Wevers RA. Clinical and biochemical characteristics of congenital disorder of glycosylation type Ic, the first recognized endoplasmic reticulum defect in N-glycan synthesis. Ann Neurol 2000;47:776 –781 In 1980, Jaeken and co-workers 1 described monozy- gotic twins with developmental retardation and several glycoprotein abnormalities. This observation initiated the delineation of a rapidly growing group of genetic disorders caused by defects in the synthesis or process- ing of N-glycans. 2 These congenital disorders of glyco- sylation (CDGs), formerly known as carbohydrate- deficient glycoprotein syndrome, present with variable clinical symptoms. Isoelectric focusing (IEF) of serum transferrin is the commonly used diagnostic test. The most frequently observed IEF pattern is characterized by an increase in the a- and disialotransferrin bands (type I). 3 Most CDG-I cases result from phosphoman- nomutase (PMM) 2 deficiency (CDG-Ia). 4–6 The common features of CDG-Ia patients are moderate to severe impairment of neurological function and vari- able dysmorphology. 7,8 More recently, patients with a mainly hepatointestinal presentation caused by a de- ficiency of phosphomannose isomerase (PMI) have been described (CDG-Ib). 9,10 –12 To date, 5 cases have been reported with a typical CDG-I transferrin IEF pattern due to a deficiency of the endoplasmic reticulum– localized a-1,3 glucosyltransferase (Fig 1). 13,14 The molecular genetic basis of CDG-Ic has been described by Imbach and colleagues. 15 In this report, we review its clinical and biochemical characteristics in 8 chil- dren and compare the clinical features with those of CDG-Ia. Patients and Methods Clinical Evaluation Eight children were studied (5 boys and 3 girls), ranging in age from 1.6 to 10.10 years (mean, 5.2 years). Four Dutch children, a pair of monozygous twins and 2 other siblings, From the *Department of Pediatrics, Heinrich-Heine University Du¨sseldorf, Germany; ²Center for Human Genetics, University of Leuven, and **Department of Pediatrics, University Hospital Gas- thuisberg, Leuven, Belgium; ‡Institute of Physiology, University of Zurich, Switzerland; §Laboratory of Pediatrics and Neurology, and i Department of Metabolic Diseases and Department of Pediatric Neurology, University Hospital Nijmegen, Nijmegen, ¶Sophia Chil- dren’s Hospital, Rotterdam, and #Department of Neurology, Igna- tius Hospital, Breda, The Netherlands. Received Nov 16, 1999, and in revised form Feb 7, 2000. Accepted for publication Feb 11, 2000. Address correspondence to Dr Wevers, University Hospital Nijme- gen, Laboratory of Pediatrics and Neurology, Institute of Neurol- ogy, PO Box 9101, NL-6500 HB Nijmegen, The Netherlands. 776 Copyright © 2000 by the American Neurological Association