Oxidative Stress in Phenylketonuria: What is the Evidence?

Abstract

Phenylketonuria (PKU) is an inborn error of amino acid metabolism caused by severe deficiency of phenylalanine hydroxylase activity, leading to the accumulation of phenylalanine and its metabolites in blood and tissues of affected patients. Phenylketonuric patients present as the major clinical feature mental retardation, whose pathomechanisms are poorly understood. In recent years, mounting evidence has emerged indicating that oxidative stress is possibly involved in the pathology of PKU. This article addresses some of the recent developments obtained from animal studies and from phenylketonuric patients indicating that oxidative stress may represent an important element in the pathophysiology of PKU. Several studies have shown that enzymatic and non-enzymatic antioxidant defenses are decreased in plasma and erythrocytes of PKU patients, which may be due to an increased free radical generation or secondary to the deprivation of micronutrients which are essential for these defenses. Indeed, markers of lipid, protein, and DNA oxidative damage have been reported in PKU patients, implying that reactive species production is increased in this disorder. A considerable set of data from in vitro and in vivo animal studies have shown that phenylalanine and/or its metabolites elicit reactive species in brain rodent. These findings point to a disruption of pro-oxidant/antioxidant balance in PKU. Considering that the brain is particularly vulnerable to oxidative attack, it is presumed that the administration of appropriate antioxidants as adjuvant agents, in addition to the usual treatment based on restricted diets or supplementation of tetrahydrobiopterin, may represent another step in the prevention of the neurological damage in PKU.

Prooxidant-antioxidant balance in patients with phenylketonuria and its correlation to biochemical and hematological parameters

“…However, the GPx activity level expresses a tight negative connection with the serum Phe level, suggesting that Phe per Se inhibits GPx activity [32]. Recent clinical and experimental studies suggest that Phe evince oxidative stress in the hippocampus and cerebral cortex of developing rats [33].…”

Mapping the functional landscape of frequentphenylalanine hydroxylase(PAH) genotypes promotes personalised medicine in phenylketonuria

“…Therefore, the PAH system suffers from a constant shortage of BH 4 . Oxidative stress35 or other environmental factors with negative impact on BH 4 availability may trigger PAH deficiency and thus may further aggravate clinical phenotypes. Taken together, alterations in BH 4 demand may add to the molecular mechanisms underlying phenotypic variability related to both disease severity and BH 4 responsiveness.…”

Oxidative Stress Parameters in Urine from Patients with Disorders of Propionate Metabolism: a Beneficial Effect of l-Carnitine Supplementation

“…Our results in this study are also in agreement with the data reported by Mc Guire et al (2009), showing a marked reduction of urinary AOx in patients with PA. Interestingly, we found that patients under therapy also presented deficiency of their urinary AOx. It is presumed that these alterations can occur because of the treatment with restricted diets (such as in phenylketonuric patients) which are poor in micronutrients necessary for the antioxidant status or, alternatively, by an unusual increase in metabolic by-products which will directly or indirectly deplete the cell's antioxidant capacity (Moyano et al 1997;Wajner et al 2004;Sitta et al 2011;Ribas et al 2011).…”