A Novel Disorder Caused by Defective Biosynthesis of N-Linked Oligosaccharides Due to Glucosidase I Deficiency

Glucosidase I is an important enzyme in N-linked glycoprotein processing, removing specifically distal α-1,2–linked glucose from the Glc 3Man 9GlcNAc 2 precursor after its en bloc transfer from dolichyl diphosphate to a nascent polypeptide chain in the endoplasmic reticulum. We have identified a glucosidase I defect in a neonate with severe generalized hypotonia and dysmorphic features. The clinical course was progressive and was characterized by the occurrence of hepatomegaly, hypoventilation, feeding problems, seizures, and fatal outcome at age 74 d. The accumulation of the tetrasaccharide Glc(α1-2)Glc(α1-3)Glc(α1-3)Man in the patient's urine indicated a glycosylation disorder. Enzymological studies on liver tissue and cultured skin fibroblasts revealed a severe glucosidase I deficiency. The residual activity was