Abnormal Hypermethylation at Imprinting Control Regions in Patients with S-Adenosylhomocysteine Hydrolase (AHCY) Deficiency

PLoS One. 2016 Mar 14;11(3):e0151261. doi: 10.1371/journal.pone.0151261. eCollection 2016.


S-adenosylhomocysteine hydrolase (AHCY) deficiency is a rare autosomal recessive disorder in methionine metabolism caused by mutations in the AHCY gene. Main characteristics are psychomotor delay including delayed myelination and myopathy (hypotonia, absent tendon reflexes etc.) from birth, mostly associated with hypermethioninaemia, elevated serum creatine kinase levels and increased genome wide DNA methylation. The prime function of AHCY is to hydrolyse and efficiently remove S-adenosylhomocysteine, the by-product of transmethylation reactions and one of the most potent methyltransferase inhibitors. In this study, we set out to more specifically characterize DNA methylation changes in blood samples from patients with AHCY deficiency. Global DNA methylation was increased in two of three analysed patients. In addition, we analysed the DNA methylation levels at differentially methylated regions (DMRs) of six imprinted genes (MEST, SNRPN, LIT1, H19, GTL2 and PEG3) as well as Alu and LINE1 repetitive elements in seven patients. Three patients showed a hypermethylation in up to five imprinted gene DMRs. Abnormal methylation in Alu and LINE1 repetitive elements was not observed. We conclude that DNA hypermethylation seems to be a frequent but not a constant feature associated with AHCY deficiency that affects different genomic regions to different degrees. Thus AHCY deficiency may represent an ideal model disease for studying the molecular origins and biological consequences of DNA hypermethylation due to impaired cellular methylation status.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alu Elements*
  • Amino Acid Metabolism, Inborn Errors / blood
  • Amino Acid Metabolism, Inborn Errors / genetics*
  • Creatine / blood
  • DNA Methylation*
  • Female
  • Genomic Imprinting*
  • Glycine N-Methyltransferase / blood
  • Glycine N-Methyltransferase / deficiency*
  • Glycine N-Methyltransferase / genetics
  • Humans
  • Infant
  • Infant, Newborn
  • Long Interspersed Nucleotide Elements*
  • Male


  • Glycine N-Methyltransferase
  • Creatine

Supplementary concepts

  • Hypermethioninemia

Grant support

Our work was supported by funds received from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement No 316289 - InnoMol, FP7-REGPOT-2012-2013-1, as well as from the German Academic Exchange Service and the Ministry of Science, Education and Sport of the Republic of Croatia (project reference number 54392779).