Oxidative stress in phenylketonuria: future directions.

Phenylketonuria represents the most prevalent inborn error of amino acid metabolism. In early diagnosed patients adequate and continued dietary treatment results in a good neurologic outcome. Natural protein and phenylalanine-restricted diet, even if rich in fruits and vegetables, represents a serious risk for nutritional deficiencies, albeit universally accepted. In the last few years, a growing number of reports have been describing oxidative stress as a concern in phenylketonuric patients. The diet itself includes good sources of dietary antioxidants (phytochemicals, some vitamins and minerals) but also a risk factor for some deficiencies (selenium, zinc, ubiquinone-10 and L-carnitine). Additionally, the extreme stringency of the diet may impose a reduced synthesis of endogenous antioxidants (like ubiquinone-10 and glutathione). Furthermore, increased phenylalanine levels, and its metabolites, may enhance the endogenous synthesis of reactive species and free radicals and/or interfere with the endogenous synthesis of enzymatic antioxidants (like glutathione peroxidase). Therefore, oxidative stress will probably increase, mainly in late diagnosed patients or in those with bad metabolic control. Considering the known association between oxidative stress, obesity and cardiovascular disease, it seems advisable to look further to the impact of oxidative stress on body macromolecules and structures (like lipoprotein oxidation), especially in phenylketonuric patients with late diagnosis or bad metabolic control, in order to prevent future increased risks. Recommendations for PKU patient's clinical follow-up improvement and educational goals are included.