Summary
Nonketotic hyperglycinemia (NKH) is a metabolic disorder with autosomal recessive inheritance, causing severe, frequently lethal, neurological symptoms in the neonatal period. The metabolic lesion of NKH is in the glycine cleavage system (GCS), a complex enzyme system with four enzyme components; P-, T-, H-, and L-protein. The enzymatic analysis revealed that 86% of the patients with NKH are deficient of P-protein activity. 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, in P-protein gene accounts for 70% of the mutant alleles in Finland where the incidence of NKH is unusually high. The immunochemical andin situ hybridization analyses revealed that the strong GCS expression was observed in rat hippocampus, olfactory bulbus, and cerebellum. The distribution resembled that ofN-methyl-d-aspartic acid (NMDA) receptor which has binding site for glycine. It is, therefore, suggested that the neurological disturbance in NKH may be caused by excitoneurotoxicity through the NMDA receptor allosterically activated by high concentration of glycine. Based on the hypothesis the NMDA antagonists such as ketamine and dextromethorphan were administered to the patients. We treated three neonatal case with dextromethorphan and it ameliorated their findings on electroencephalogram and behavior in two out of three patients. Thus the GCS is suggested to play a role in regulation of glycine level around the NMDA receptor.
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Abbreviations
- NKH:
-
nonketotic hyperglycinemia
- GCS:
-
glycine cleavage system
- PCR:
-
polymerase chain reaction
- EEG:
-
electroencephalogram
- NMDA:
-
N-methyl-d-aspartic acid
References
Craigen WJ (1996): Leigh disease with deficiency of lipoamide dehydrogenase: treatment failure with dichloroacetate. Pediatr Neurol14: 69–71
Fujiwara K, Okamura-Ikeda K, Hayasaka K, Motokawa Y (1991): The primary structure of human H-protein of the glycine cleavage system deduced by cDNA cloning. Biochem Biophys Res Commun176: 711–716
Fujiwara K, Okamura-Ikeda K, Motokawa Y (1986): Chicken liver H-protein, a component of the glycine cleavage system. Amino acid sequence and identification of the N epsilonlipoyllysine residue. J Biol Chem261: 8836–8841
Fujiwara K, Okamura-Ikeda K, Motokawa Y (1987): Amino acid sequence of the phosphopyridoxyl peptide from P-protein of the chicken liver glycine cleavage system. Biochem Biophys Res Commun149: 621–627
Hamosh A, Johnston MV, Valle D (1995): Nonketotic hyperglycinemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds). The metabolic and molecular basis of inherited disease. McGraw-Hill, New York, pp 1337–1348
Hamosh A, McDonald JW, Valle D, Francomano CA, Niedermeyer E, Johnston MV (1992): Dextromethorphan and high-dose benzoate therapy for nonketotic hyperglycinemia in an infant. J Pediatr121: 131–135
Hayasaka K, Nanao K, Takada G, Okamura-Ikeda K, Motokawa Y (1993): Isolation and sequence determination of cDNA encoding human T-protein of the glycine cleavage system. Biochem Biophys Res Commun192: 766–771
Hayasaka K, Tada K, Fueki N, Nakamura Y, Nyhan WL, Schmidt K, Packman S, Seashore MR, Haan E, Danks DM,et al. (1987): Nonketotic hyperglycinemia: analyses of glycine cleavage system in typical and atypical cases. J Pediatr110: 873–877
Hayasaka K, Tada K, Kikuchi G, Winter S, Nyhan WL (1983): Nonketotic hyperglycinemia: two patients with primary defects of P-protein and T-protein, respectively, in the glycine cleavage system. Pediatr Res17: 967–970
Iwama H, Takahashi K, Kure S, Hayashi F, Narisawa K, Tada K, Mizoguchi M, Takashima S, Tomita U, Nishikawa T (1997): Depletion of cerebral D-serine in non-ketotic hyperglycinemia: possible involvement of glycine cleavage system in control of endogenous D-serine. Biochem Biophys Res Commun (in press)
Kikuchi G (1973): The glycine cleavage system: composition, reaction mechanism, and physiological significance. Mol Cell Biochem1: 169–187
Kikuchi G, Hiraga K, Yoshida T (1980): Role of the glycine-cleavage system in glycine and serine metabolism in various organs. Biochem Soc Trans8: 504–506
Koyata H, Hiraga K (1991): The glycine cleavage system: structure of a cDNA encoding human H-protein, and partial characterization of its gene in patients with hyperglycinemias. Am J Hum Genet48: 351–361
Kume A, Koyata H, Sakakibara T, Ishiguro Y, Kure S, Hiraga K (1991): The glycine cleavage system. Molecular cloning of the chicken and human glycine decarboxylase cDNAs and some characteristics involved in the deduced protein structures. J Biol Chem266: 3323–3329
Kume A, Kure S, Tada K, Hiraga K (1988): The impaired expression of glycine decarboxylase in patients with hyperglycinemias. Biochem Biophys Res Commun154: 292–297
Kure S, Koyata H, Kume A, Ishiguro Y, Hiraga K (1991a): The glycine cleavage system. The coupled expression of the glycine decarboxylase gene and the H-protein gene in the chicken. J Biol Chem266: 3330–3334
Kure S, Narisawa K, Tada K (1991b): Structural and expression analyses of normal and mutant mRNA encoding glycine decarboxylase: Three-base deletion in mRNA causes nonketotic hyperglycinemia. Biochem Biophys Res Commun174: 1176–1182
Kure S, Narisawa K, Tada K (1992a): Enzymatic diagnosis of nonketotic hyperglycinemia with lymphoblasts. J Pediatr120: 95–98
Kure S, Narisawa K, Tada K (1995): The glycine cleavage system in astrocytes: Its physiological role revealed by study of hyperglycinemia. J Neurochem65: S125
Kure S, Takayanagi M, Narisawa K, Tada K, Leisti J (1992b): Identification of a common mutation in Finnish patients with nonketotic hyperglycinemia. J Clin Invest90: 160–164
Motokawa Y, Kikuchi G (1972): Isolation and partial characterization of the components of the reversible glycine cleavage system of rat liver mitochondria. J Biochem72: 1281–1284
Nanao K, Takada G, Takahashi E, Seki N, Komatsu Y, Okamura-Ikeda K, Motokawa Y, Hayasaka K (1994): Structure and chromosomal localization of the aminomethyltransferase gene (AMT). Genomics19: 27–30
Ohya Y, Ochi N, Mizutani N, Hayakawa C, Watanabe K (1991): Nonketotic hyperglycinemia: Treatment with NMDA antagonist and consideration of neuropathogenesis. Pediatr Neurol7: 65–68
Okamura-Ikeda K, Fujiwara K, Yamamoto M, Hiraga K, Motokawa Y (1991): Isolation and sequence determination of cDNA encoding T-protein of the glycine cleavage system. J Biol Chem266: 4917–4921
Okamura-Ikeda K, Ohmura Y, Fujiwara K, Motokawa Y (1993): Cloning and nucleotide sequence of the gcv operon encoding theEscherichia coli glycine-cleavage system. Eur J Biochem216: 539–548
Sato K, Yoshida S, Fujiwara K, Tada K, Tohyama M (1991): Glycine cleavage system in astrocytes. Brain Res567: 64–70
Tada K (1987): Nonketotic hyperglycinemia: clinical and metabolic aspects. Enzyme38: 27–35
Tada K, Hayasaka K (1987): Nonketotic hyperglycinemia: clinical and biochemical aspects. Eur J Pediatr146: 221–227
Tada K, Narisawa K, Yoshida T, Yokoyama K, Nakagawa H, Tanno K, Mochizuki K, Arakawa T, Yoshida T, Kikuchi G (1969): Hyperglycinemia: a defect in glycine cleavage reaction. Tohoku J Exp Med98: 289–296
v. Wendt L, Hirvasniemi A, Similä S (1979): Nonketotic hyperglycinemia: A genetic study of 13 Finish families. Clin Genet15: 411–417
Yamamoto M, Koyata H, Matsui C, Hiraga K (1991): The glycine cleavage system: Occurrence of two types of chicken H-protein mRNAs presumably formed by the alternative use of the polyadenylation consensus sequences in a single exon. J Biol Chem266: 3317–3322
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Kure, S., Tada, K. & Narisawa, K. Nonketotic hyperglycinemia: Biochemical, molecular, and neurological aspects. Jap J Human Genet 42, 13–22 (1997). https://doi.org/10.1007/BF02766917
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DOI: https://doi.org/10.1007/BF02766917
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