Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia

Shigeo Kure, Kumi Kato, Agirios Dinopoulos, Chuck Gail, Ton J. DeGrauw, John Christodoulou, Vladimir Bzduch, Rozalia Kalmanchey, Gyorgy Fekete, Alex Trojovsky, Barbara Plecko, Galen Breningstall, Jun Tohyama, Yoko Aoki, Yoichi Matsubara

Research output: Contribution to journalArticlepeer-review

69 Citations (Scopus)


Nonketotic hyperglycinemia (NKH) is an inborn error of metabolism characterized by accumulation of glycine in body fluids and various neurological symptoms. NKH is caused by deficiency of the glycine cleavage multi-enzyme system with three specific components encoded by GLDC, AMT and GCSH. We undertook the first comprehensive screening for GLDC, AMT and GCSH mutations in 69 families (56, six, and seven families with neonatal, infantile, and late-onset type NKH, respectively). GLDC or AMT mutations were identified in 75% of neonatal and 83% of infantile families, but not in late-onset type NKH. No GCSH mutation was identified in this study. GLDC mutations were identified in 36 families, and AMT mutations were detected in 11 families. In 16 of the 36 families with GLDC mutations, mutations were identified in only one allele despite sequencing of the entire coding regions. The GLDC gene consists of 25 exons. Seven of the 32 GLDC missense mutations were clustered in exon 19, which encodes the cofactor-binding site Lys754. A large deletion involving exon 1 of the GLDC gene was found in Caucasian, Oriental, and black families. Multiple origins of the exon 1 deletion were suggested by haplotype analysis with four GLDC polymorphisms. This study provides a comprehensive picture of the genetic background of NKH as it is known to date.

Original languageEnglish
Pages (from-to)343-352
Number of pages10
JournalHuman mutation
Issue number4
Publication statusPublished - 2006 Apr 1


  • AMT
  • GCSH
  • GLDC
  • Genotype-phenotype
  • Glycine cleavage system
  • Glycine encephalopathy
  • Mutation spectrum
  • NKH
  • Nonketotic hyperglycinemia

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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