WHAT IS Congenital disorders of glycosylation-Ia?

Congenital disorders of glycosylation-Ia are the most frequent type of congenital disorders of glycosylation. This condition affects the nervous system as well as other organs. The estimated incidence of congenital disorders of glycosylation-Ia is higher than the number of identified cases, therefore underdiagnosis of this heterogeneous disorder is probable. Neurologic and biologic signs are hallmarks for the identification of patients with congenital disorders of glycosylation-Ia.

CDG-Ia is the most common type of CDG, with more than 600 cases identified worldwide. The patients have moderate to severe psychomotor retardation, hypotonia, dysmorphic features, failure to thrive, liver dysfunction, coagulopathy, abnormal endocrine functions, and a pronounced susceptibility to infection. Scores of mutations have been found in phosphomannomutase 2 (PMM2), the defective gene in CDG-Ia. PMM2 encodes an enzyme that catalyzes the conversion of Man-6-P to Man-1-P, which is a precursor required for the synthesis of GDP-mannose (GDP-Man) and dolichol-P-mannose (Dol-P-Man). Both donors are substrates for the mannosyltransferases involved in the synthesis of Glc3Man9GlcNAc2-PP-Dol and their levels are decreased in CDG-Ia patients. Patients have hypomorphic alleles and complete loss of activity is lethal. In fact, mouse embryos lacking Pmm2 die 2–4 days after fertilization, whereas those with homozygous hypomorphic alleles survive. There are currently no therapeutic options for CDG-Ia patients. In vitro studies suggested that supplements of mannose might improve glycosylation, but mannose therapy for CDG-Ia patients is ineffective.
(From: Essentials of glycobiology , chapter 41: Genetic Disorders of Glycosylation. Authors: Hudson H. Freeze and Harry Schachter)