NONKETOTIC HYPERGLYCINEMIA - MOLECULAR LESION, DIAGNOSIS AND PATHOPHYSIOLOGY

Non-ketotic hyperglycinaemia (NKH) is a well-recognized metabolic caus e of life-threatening illness in the neonate. The fundamental defect i s in the glycine cleavage system, which consists of four protein compo nents. Our study revealed that the majority of NKH patients had a spec ific defect in P-protein (glycine decarboxylase). The primary lesion o f NKH at gene level was investigated, using cDNA encoding human glycin e decarboxylase. A three-base deletion resulting in deletion of Phe756 was found in a Japanese patient with NKH. The majority of NKH patient s in Finland, where there is a high incidence of NKH, were found to be due to a common mutation, a point mutation resulting in the amino aci d substitution of Ile564 for Ser564. Prenatal diagnosis is feasible by determining the activity of the glycine cleavage system and is also p ossible by DNA analysis. Recent findings suggest that a high concentra tion of glycine in the brain may contribute to the pathophysiology of NKH by overactivating N-methyl-D-aspartate receptors allosterically, w hich may result in intracellular calcium accumulation, DNA fragmentati on and neuronal death. These provide the possibility that early treatm ent with N-methyl-D-aspartate receptor antagonist may prevent brain da mage in NKH.