Demethylation of the promoter region of GPX3 in a newborn with classical phenylketonuria

Objectives: Phenylketonuria (PKU) is characterized by a high phenylalanine (phe) in plasma and oxidative stress. However, the monitoring of oxidative stress in newborns with PKU using the activity levels of antioxidant enzymes is not optimal. We investigated the possibility of monitoring an increased reactive oxygen species (ROS) production using DNA methylation changes of an oxidative stress response element in the promoter region of an enzymatic antioxidant gene.

Design and methods: Using DNA extracted from blood leukocytes, the cytosine phosphodiester bond guanine positions of an overlapping CCAAT box/metal response element (CGATTGGCTG) of the glutathione peroxidase 3 promoter activated by oxidative stimuli and expressed in plasma were analysed for methylation changes in 20 newborns with hyperphenylalaninemia and 20 healthy controls.

Results: A demethylated allele was detected in a PKU patient at a phe level of 465μmol/L on day 2 after birth, but not in other patients (phe<465μmol/L, ≥day 2 after birth; phe>465μmol/L, ≥day 3 after birth) and healthy controls (phe<465μmol/L, ≥day 2 after birth).

Conclusions: The detection of the demethylated allele could be time and phe concentration dependent. The demethylated allele is suggested as an early epigenetic marker for an extracellular monitoring of an increased ROS production in newborns with PKU.