Congenital disorders of N-glycosylation

These disorders, first identified by Prof J. Jaeken (Kuleuven), are due to enzymatic defects in the pathway leading to the formation of N-glycan. This pathway involves steps taking place in the cytosol (formation of the NDP-sugars), the endoplasmic reticulum (the formation and transfer of the oligosaccharide on the nascent protein, and the first steps of its trimming), and the Golgi apparatus (remodeling of the oligosaccharide). The most frequent defect is phosphomannomutase deficiency, first identified in 1995 [1] and due to mutations in the phosphomannomutase 2 gene [3]. More then a dozen defects are presently known. Our group is involved in the European consortium Euroglycan, whose aim is to identify the enzymatic and genetic defects in unresolved cases of CDG.

2-Hydroxyglutaric acidurias

D- and L-2-hydroxyglutaric acidurias are distinct neurometabolic diseases characterized by the accumulation of abnormal amounts of either D- or L-2-hydroxyglutarate in cerebrospinal fluid, blood and urine. The biochemical lesions responsible for these disorders are not identified, largely due to the fact that the enzymes responsible for the utilization of these two 2-hydroxyacids are not well characterized and that their molecular identity is unknown. We have recently identified an FAD-linked enzyme that converts D-2-hydroxyglutarate to alpha-ketoglutarate [9]. It is likely that this enzyme, which displays a high affinity for its subtrate (Km ≈ 3 mM) for its substrate, is deficient in D-2-hydroxyglutaric aciduria.