Antioxidant treatment strategies for hyperphenylalaninemia

Abstract

Hyperphenylalaninemia (HPA) leads to increased oxidative stress in patients with phenylketonuria (PKU) and in animal models of PKU. Early diagnosis and immediate adherence to a phenylalanine-restricted diet prevents HPA and, consequently, severe brain damage. However, treated adolescent and adult PKU patients have difficulties complying with the diet, leading to an oscillation of phenylalanine levels and associated oxidative stress. The brain is especially susceptible to reactive species, and oxidative stress might add to the impaired cognitive function found in these patients. The restricted PKU diet has a very limited nutrient content from natural foods and almost no animal protein, which reduces the intake of important compounds. These specific compounds can act as scavengers of reactive species and can be co-factors of antioxidant enzymes. Supplementation with nutrients, vitamins, and tetrahydropterin has given quite promising results in patients and animal models. Antioxidant supplementation has been studied in HPA, however there is no consensus about its always beneficial effects. In this way, regular exercise could be a beneficial addition on antioxidant status in PKU patients. A deeper understanding of PKU molecular biochemistry, and genetics, as well as the need for improved targeted treatment options, could lead to the development of new therapeutic strategies.

Hyperphenylalaninemia Correlated with Global Decrease of Antioxidant Genes Expression in White Blood Cells of Adult Patients with Phenylketonuria

“…Physical exercise has been shown to improve brain function by preventing oxidative stress in PKU . Several antioxidant supplementations have been evaluated and may be a complement or an alternative to a restrictive diet for adolescent and adult PKU patients with poor compliance (Mazzola et al 2013). In this way, supplementation with L-carnitine and selenium seems to prevent oxidative stress observed in hyperphenylalaninemia .…”

“…Phenylketonuria (PKU, OMIM #26160) is an autosomal recessive disease caused by the deficiency of phenylalanine hydroxylase activity leading to an accumulation of phenylalanine (Phe) and its metabolites in blood and tissues of affected patients (Krause et al 1985;Mazzola et al 2013). Neonatal newborn mass-screening of this disorder allows early diagnosis and consequently a better and earlier dietary management leading to a normal development of PKU children (Groselj et al 2014).…”

“…In PKU, accumulation of Phe and/or its metabolites may lead to a disturbance of redox homeostasis (Artuch et al 2004;Mazzola et al 2013). Some studies showed an increase of lipoperoxidation markers (Sanayama et al 2011) and DNA damages (Sitta et al 2009), or a reduction of various antioxidant compounds, especially selenium, coenzyme Q10, or antioxidant system of glutathione (Menzel et al 1983;Sitta et al 2006;Sanayama et al 2011).…”

“…Understanding and characterization of oxidative mechanisms in PKU are essential for management and treatment of the disease. It remains crucial to assess whether oxidative unbalance may be associated with plasma Phe concentration, and potentially controlled by a diet limiting the plasma Phe concentration and/or antioxidants supplementation strategy, which may be useful for PKU management and patients' outcome (Mazzola et al 2013).…”

The oxidative molecular regulation mechanism of NOX in children with phenylketonuria

“…Studies demonstrated that T‐AOC was decreased in PKU (Sitta et al, 2009). GSH was reported to be decreased in erythrocytes, hippocampus and cerebral cortex by the administration of Phe in vitro to the hippocampus and cerebral cortex of rat brains (Mazzola et al, 2013; Fernandes et al, 2010). In the current study, it was worth to note that decreased T‐AOC and GSH in PKU patients seemed to correlate negatively with Phe level.…”