Abstract
Abstract Objectives Phenylketonuria (PKU) is a proteinopathy due to the deficiency of phenylalanine hydroxylase (PAH) enzyme. The pathological elevation of phenylalanine (Phe) and its metabolites in PKU is linked to neurological hallmarks and mental disabilities. The aim of this study was to examine the hypothesis that high levels of Phe caused endoplasmic reticulum (ER) stress in PKU patients. Methods We primarily evaluated ER stress markers glucose-regulated protein78 (GRP78) and C/-EBP homologous protein (CHOP), and thiobarbituric acid-reactive substances (TBARS) as a biomarker of oxidative stress in leukocytes and correlated it with blood Phe values from patients with PKU. Patients in this study were selected from individuals who were diagnosed with PKU as a result of the national neonatal screening program and undergone treatment at our university hospital. The subjects were divided into four groups: healthy controls, patients with hyperphenylalaninemia (HPA), BH4-responsive patients with PKU and patients with classic PKU. GRP78, CHOP and TBARS levels were estimated in leukocytes isolated from whole blood of subjects, Phe and tyrosine levels were determined in plasma. Results The levels of Phe in BH4-responsive PKU and classic PKU groups were statistically higher as compared to healthy controls, and Phe levels were higher in classic PKU compared to HPA group. CHOP levels were elevated by 35.3% in BH4-responsive group compared to control. GRP78, CHOP and TBARS showed no statistical differences between control and patient groups. GRP78 was also negatively correlated with Phe levels. Conclusions These results suggested that blood Phe concentrations might not be associated to ER stress in white blood cells obtained from the PKU patient groups under treatment.
Highlights
Phenylketonuria (PKU), a well-known misfolding disease, is an inborn error of L-phenylalanine (Phe) metabolism characterized by mutations in the Phe hydroxylase (PAH) gene
Phe concentrations were statistically higher in BH4-responsive PKU and classic PKU groups compared to healthy controls (p=0.006, p=0.001), and in classic PKU group according to HPA group (p=0.026)
The results demonstrated that, there was no significant difference between control subjects and patient groups in terms of glucose-regulated protein78 (GRP78) and C/-EBP homologous protein (CHOP) levels related to the endoplasmic reticulum (ER) stress in leukocytes (p>0.05)
Summary
Phenylketonuria (PKU), a well-known misfolding disease, is an inborn error of L-phenylalanine (Phe) metabolism characterized by mutations in the Phe hydroxylase (PAH) gene. Normal blood Phe concentration is 50–110 μmol/L. The untreated PKU patients who depict a level of 120–600 μmol/L of Phe prior to starting therapy are classified as having mild HPA (sometimes those with plasma Phe concentration 150–360 μmol/L on newborn screening called as HPA). Individuals with Phe concentrations ranging from 600–1,200 μmol/L are classified as mild PKU (occasionally those with values of 900–1,200 μmol/L are termed as a moderate classification). Phe levels ranging over 1,200 μmol/L is called classic PKU [1, 4, 5]. Patients with Phe levels >360 μmol/L should be checked for responsiveness to BH4. A decline in blood Phe value of 30% or more than baseline shows response to BH4 therapy [6, 7]
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