Metabolic Brain Disease

, Volume 34, Issue 1, pp 373–376 | Cite as

A novel intronic homozygous mutation in the AMT gene of a patient with nonketotic hyperglycinemia and hyperammonemia

  • Sarah Silverstein
  • Aravindhan Veerapandiyan
  • Caroline Hayes-Rosen
  • Xue Ming
  • Jeffrey KornitzerEmail author
Short Communication


Nonketotic Hyperglycinemia is an autosomal recessive disorder characterized by defects in the mitochondrial glycine cleavage system. Most patients present soon after birth with seizures and hypotonia, and infants that survive the newborn period often have profound intellectual disability and intractable seizures. Here we present a case report of a 4-year-old girl with NKH as well as hyperammonemia, an uncommon finding in NKH. Genetic analysis found a previously unreported homozygous mutation (c.878–1 G > A) in the AMT gene. Maximum Entropy Principle modeling predicted that this mutation most likely breaks the splice site at the border of intron 7 and exon 8 of the AMT gene. Treatment with L-Arginine significantly reduced both the proband’s glycine and ammonia levels, in turn aiding in control of seizures and mental status. This is the first time the use of L-Arginine is reported to successfully treat elevated glycine levels.


Glycine encephalopathy Genetics Hyperammonemia L-arginine Maximum entropy principle modeling 


Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to disclose.


  1. Applegarth DA, Toone JR (2001) Nonketotic hyperglycinemia (Glycine encephalopathy): laboratory diagnosis. Mol Genet Metab 74:139–146. CrossRefPubMedGoogle Scholar
  2. Applegarth DA, Toone JR (2004) Glycine encephalopathy (nonketotic hyperglycinaemia): review and update. J Inherit Metab Dis 27(3):417–422. CrossRefPubMedGoogle Scholar
  3. Belcastro V, Barbarini M, Barca S, Mauro I (2016) A novel AMT gene mutation in a newborn with nonketotic hyperglycinemia and early myoclonic encephalopathy. Eur J Paediatr Neurol 20(1):192–195. CrossRefPubMedGoogle Scholar
  4. Chang Y-T, Lin WD, Chin ZN, Wang CS, Chou IC, Kuo HT, Tsai FJ (2012) Nonketotic hyperglycinemia: a case report and brief review. Biomedicine 2(2):80–82. CrossRefGoogle Scholar
  5. Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C (2009) Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37(9):e67. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Eagle H (1959) Amino acid metabolism in mammalian cell cultures. Science 130(3373):432–437 Available at: CrossRefGoogle Scholar
  7. Fahey JL (1957) Toxicity and blood ammonia rise resulting from intravenous amino acid administration in man: the protective effect of l-arginine. J Clin Invest 36(12):1647–1655CrossRefGoogle Scholar
  8. Farriaux J, Morel P, Hommes F (1976) Letter to the editor: neonketotic hyperglycinemia with increased proprionic acid excretion and hyperammonemia. N Engl J Med 294(10):558–559PubMedGoogle Scholar
  9. Gross MD, Eggen MA, Simon AM, van Pilsum JF (1986) The purification and characterization of human kidney L-arginine:glycine amidinotransferase. Arch Biochem Biophys 251(2):747–755 Available at: CrossRefGoogle Scholar
  10. Iqbal M, Prasad M, Mordekar SR (2015) Nonketotic hyperglycinemia case series. J Pediatr Neurosci 10(4):355–358. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Kikuchi BG et al (2008) Glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia. 84:246–263.
  12. Kure S, Tada K, Narisawa K (1997) Nonketotic hyperglycinemia: biochemical, molecular, and neurological aspects. Jpn J Hum Genet 42(1):13–22. CrossRefPubMedGoogle Scholar
  13. Madu AE, Oliver L (2013) Non-ketotic hyperglycinaemia: case report and review of medical literature. J Matern Fetal Neonatal Med 26(5):537–539. CrossRefPubMedGoogle Scholar
  14. Okamura-Ikeda K, Hosaka H, Yoshimura M, Yamashita E, Toma S, Nakagawa A, Fujiwara K, Motokawa Y, Taniguchi H (2005) Crystal structure of human T-protein of glycine cleavage system at 2.0 ?? Resolution and its implication for understanding non-ketotic hyperglycinemia. J Mol Biol 351(5):1146–1159. CrossRefPubMedGoogle Scholar
  15. Schiffmann R, Boneh A, Ergaz Z, Glick B (1992) Nonketotic hyperglycinemia presenting with pin-point pupils and hyperammonemia. Isr J Med Sci 28(2):91–93 Available at: PubMedGoogle Scholar
  16. Toone JR, Applegarth DA, Coulter-Mackie MB, James ER (2000) Biochemical and molecular investigations of patients with nonketotic hyperglycinemia. Mol Genet Metab 70(2):116–121. CrossRefPubMedGoogle Scholar
  17. Toone, J. R. et al. (2001) Identification of the first reported splice site mutation (IVS7-1G-->A) in the aminomethyltransferase (T-protein) gene (AMT) of the glycine cleavage complex in 3 unrelated families with nonketotic hyperglycinemia. Hum Mutat, 17(July), p. 76.<76::AID-HUMU17>3.0.CO;2-0
  18. Toone JR, Applegarth DA, Levy HL, Coulter-Mackie MB, Lee G (2003) Molecular genetic and potential biochemical characteristics of patients with T-protein deficiency as a cause of glycine encephalopathy (NKH). Mol Genet Metab 79(4):272–280. CrossRefPubMedGoogle Scholar
  19. Tsai KN, Wang D (2012) Identification of activated cryptic 5′ splice sites using structure profiles and odds measure. Nucleic Acids Res 40(10):e73. CrossRefPubMedPubMedCentralGoogle Scholar
  20. von Wendt, L. et al. (1978) Nonketotic hyperglycinemia: a clinical analysis of 19 Finnish patients.. Monogr Hum Genet, 9(Jan), pp. 58–64Google Scholar
  21. Wada Y, Tada K, Takada G, Omura K, Yoshida T (1972) Hyperglycinemia associated with hyperammonemia: in vitro glycine cleavage in liver. Pediatr Res 6:622–625PubMedGoogle Scholar
  22. Walker JL, Oliver DJ (1986) Glycine decarboxylase multienzyme complex. Purification and partial characterization from pea leaf mitochondria. J Biol Chem 261(5):2214–2221. CrossRefPubMedGoogle Scholar
  23. Yeo G, Burge CB (2004) Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11(2–3):377–394. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeurologyRutgers University-New Jersey Medical SchoolNewarkUSA
  2. 2.Department of Pediatrics, Division of Neurology, Arkansas Children’s HospitalUniversity of Arkansas for Medical SciencesLittle RockUSA

Personalised recommendations