Cognition after a 4-week high phenylalanine intake in adults with phenylketonuria - a randomized controlled trial

Background: Phenylketonuria (PKU) is an autosomal recessive metabolic disorder characterized by increased phenylalanine (Phe) concentrations in the blood and brain. Despite wide agreement on treatment during childhood, recommendations for adults are still controversial. Objective: To assess the impact of a 4-week increase in Phe intake (simulating normal dietary Phe consumption) on cognition, mood, and depression in early-treated adults with PKU in a double-blind, randomized controlled trial (RCT). Methods: In a single -site crossover trial, 30 adult patients with classical PKU diagnosed at birth were recruited. All patients underwent a 4-week period of oral Phe administration (1500 - 3000 mg Phe/d) and a 4-week placebo period in a randomly assigned order with age, sex, and place of usual medical care as strati fi cation factors. Analyses were based on the intention-to-treat (ITT) and per protocol (PP) approach to claim noninferiority (noninferiority margin - 4%), with working memory accuracy as the primary endpoint and additional cognitive domains, mood, and depression as secondary endpoints. Results: For the primary endpoint, a 4-week increase of Phe intake was noninferior to placebo with respect to working memory accuracy in both the ITT [point estimate 0.49; lower limit 95% con fi dence interval (CI): - 1.99] and the PP analysis (point estimate - 1.22; lower limit 95% CI: - 2.60). Secondary outcomes (working memory reaction time, manual dexterity, mood, and depression) did not signi fi cantly differ between the Phe and placebo period, except for sustained attention (point estimate 31.0; lower limit 95% CI: 9.0). Adverse events were more frequent during the Phe than during the placebo period (95% CI: 1.03, 2.28, P = 0.037). Conclusions: In early-treated adult patients with PKU, a 4-week high Phe intake was noninferior to continuing Phe restriction regarding working memory accuracy, and secondary outcomes did not differ except for sustained attention. Longer-term RCTs are required to determine whether low Phe levels need to be maintained throughout different periods of adulthood. This trial was registered at the clinicaltrials.gov as NCT03788343.