Non-ketotic hyperglycinaemia: Molecular lesion, diagnosis and pathophysiology

Summary

Non-ketotic hyperglycinaemia (NKH) is a well-recognized metabolic cause of life-threatening illness in the neonate. The fundamental defect is in the glycine cleavage system, which consists of four protein components. Our study revealed that the majority of NKH patients had a specific defect in P-protein (glycine decarboxylase). The primary lesion of NKH at gene level was investigated, using cDNA encoding human glycine decarboxylase. A three-base deletion resulting in deletion of Phe⁷⁵⁶ was found in a Japanese patient with NKH. The majority of NKH patients 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 acid substitution of Ile⁵⁶⁴ for Ser⁵⁶⁴. Prenatal diagnosis is feasible by determining the activity of the glycine cleavage system and is also possible by DNA analysis. Recent findings suggest that a high concentration of glycine in the brain may contribute to the pathophysiology of NKH by overactivatingN-methyl-d-aspartate receptors allosterically, which may result in intracellular calcium accumulation, DNA fragmentation and neuronal death. These provide the possibility that early treatment withN-methyl-d-aspartate receptor antagonist may prevent brain damage in NKH.