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Background The population of adult patients with early-treated phenylketonuria (PKU) following newborn screening is growing substantially. The ideal target range of blood Phenylalanine (Phe) levels in adults outside pregnancy is a matter of debate. Therefore, prospective intervention studies are needed to evaluate the effects of an elevated Phe concentration on cognition and structural, functional and neurometabolic parameters of the brain. Methods The PICO (Phenylalanine and Its Impact on Cognition) Study evaluates the effect of a 4-week Phe load on cognition and cerebral parameters in adults with early-treated PKU in a double-blind, randomized, placebo-controlled, crossover, non-inferiority trial. Participants: 30 adult patients with early-treated PKU and 30 healthy controls comparable to patients with regard to age, sex and educational level will be recruited from the University Hospitals Bern and Zurich, Switzerland. Patients are eligible for the study if they are age ≥18 years and have PKU diagnosed after a positive newborn screening and treated with a Phe-restricted diet starting within the first 30 days of life. Intervention: The cross-over intervention consists of a 4-week oral Phe or placebo administration in patients with PKU. The study design mimics a Phe-restricted and a Phe-unrestricted diet using a double-blinded, placebo-controlled approach. Objectives: The primary objective of the PICO Study is to prospectively assess whether a temporarily elevated Phe-level influences cognitive performance (working memory assessed with a n-back task) in adults with early-treated PKU. As secondary objective, the PICO Study will elucidate cerebral (fMRI: neural activation during a n-back task; rsfMRI: functional connectivity at rest; DTI: white matter integrity; ASL: cerebral blood flow) and neurometabolic mechanisms (cerebral Phe-level), which accompany changes in Phe concentration. Cognition, structural and functional parameters of the brain of adult patients with early-treated PKU will be cross-sectionally compared to healthy controls. All assessments will take place at the University Hospital Bern, Switzerland. Randomization: Central randomization will be used to assign participants to the different treatment arms with age, sex and center serving as stratification factors. Randomization lists will be generated by an independent statistician. Blinding: All trial personnel but the statistician generating the randomization list and the personnel at the facility preparing the interventional product are blinded to the assigned treatment. |
