NONKETOTIC HYPERGLYCINEMIA - BIOCHEMICAL, MOLECULAR, AND NEUROLOGICALASPECTS

Nonketotic hyperglycinemia (NKH) is a metabolic disorder with autosoma l recessive inheritance, causing severe, frequently lethal, neurologic al symptoms in the neonatal period. The metabolic lesion of NKH is in the glycine cleavage system (GCS), a complex enzyme system with four e nzyme components; P-, T-, H-, and L-protein. The enzymatic analysis re vealed that 86% of the patients with NKH are deficient of P-protein ac tivity. The cDNA clones encoding all four components were isolated and their primary structures were determined. Several mutations have been identified in P- and T-protein genes: One missense mutation, S564I, i n P-protein gene accounts for 70% of the mutant alleles in Finland whe re the incidence of NKH is unusually high. The immunochemical and in s itu hybridization analyses revealed that the strong GCS expression was observed in rat hippocampus, olfactory bulbus, and cerebellum. The di stribution resembled that of N-methyl-D-aspartic acid (NMDA) receptor which has binding site for glycine. It is, therefore, suggested that t he neurological disturbance in NKH may be caused by excitoneurotoxicit y through the NMDA receptor allosterically activated by high concentra tion of glycine. Based on the hypothesis the NMDA antagonists such as ketamine and dextromethorphan were administered to the patients. We tr eated three neonatal case with dextromethorphan and it ameliorated the ir findings on electroencephalogram and behavior in two out of three p atients. Thus the GCS is suggested to play a role in regulation of gly cine level around the NMDA receptor.