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.