Phenylketonuria (PKU) is a rare autosomal recessive disorder caused by deficiency of the phenylalanine hydroxylase enzyme leading to an impaired conversion of the amino acid phenylalanine (Phe) to tyrosine. Increased Phe concentrations in blood and brain during childhood can lead to severe intellectual disability, epilepsy and behavioral problems. However, since the introduction of newborn screening and early treatment with a dietary restriction of Phe (low protein diet) and Phe-free protein substitutes (amino acid mixtures) initiated soon after birth, patient with PKU no longer develop profound and irreversible intellectual disability. While there is a wide agreement on the treatment strategy and target Phe concentrations in childhood, no consensus on the safe Phe concentrations in adulthood has been reached so far. Traditionally, the low protein diet had been enforced only during childhood and adolescence, leaving adult patients with PKU off-diet. Over the last decade, observational and cross-sectional studies associated high Phe in early-treated adult patients with cognitive problems, psychiatric symptoms and behavioral abnormalities. These association studies and one small interventional study led to substantially differing recommendations of national and international guidelines with regard to Phe target levels in adult patients with PKU. One of these guidelines is the highly controversial grade D recommendation of the most recent European guidelines to keep Phe concentrations below 600 μmol/L throughout adulthood. Consequently, the recommendations are not only unequally accepted by the treating metabolic specialists, more than 50 % of adults with PKU exhibit substantial difficulty in maintaining the compliance necessary to reach the recommended target Phe concentrations. Therefore, prospective intervention studies in adult patients with PKU are strongly needed to evaluate the effects of dietary restrictions on cognition, cerebral markers and quality of life. The PICO-Study aims at adding evidence to current guidelines and improving treatment recommendations. To this end, adult patients with PKU will participate in a randomized, placebo-controlled, double-blind, crossover, non-inferiority trial. With the intervention, the project evaluates the impact of temporarily elevated blood Phe levels on cognition and functional properties of the brain of adult patients. Results of the PICO-Study will help to increase knowledge about impaired cognitive functioning and neural abnormalities in adult patients with PKU and will improve guidelines on dietary treatment in these patients. Such guidelines can greatly influence clinical routine as well as patients' adherence to their diet and ultimately their quality of life.
The PICO-Study is a randomized, placebo-controlled, crossover, non-inferiority trial conducted to add evidence to the current European treatment guidelines for adult patients with phenylketonuria.