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Cognition after a 4-week high phenylalanine intake in adults with phenylketonuria - a randomized controlled trial
Roman Trepp1, Raphaela Muri2, Stephanie Maissen-Abgottspon1
1Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
Insights
Phenylketonuria (PKU) patients showed no cognitive decline with increased phenylalanine intake. Further research is needed to confirm long-term effects of dietary phenylalanine in adults with PKU.
Area of Science:
- Metabolic Disorders
- Neuroscience
- Clinical Trials
Background:
- Phenylketonuria (PKU) is an inherited metabolic disorder causing high phenylalanine (Phe) levels.
- Current PKU treatment guidelines for adults remain debated.
- Early-treated adults with PKU face uncertainty regarding optimal Phe management.
Purpose of the Study:
- To evaluate the cognitive and mood effects of a temporary increase in dietary phenylalanine in adults with PKU.
- To compare working memory, mood, and depression in PKU patients on restricted vs. liberalized Phe diets.
- To conduct a double-blind, randomized controlled trial (RCT) to assess Phe intake impact.
Main Methods:
- A single-site, double-blind, randomized crossover trial involving 30 early-treated adult PKU patients.
- Participants received either increased Phe intake (1500-3000 mg/day) or a placebo for 4 weeks, followed by a crossover.
- Working memory accuracy was the primary endpoint, with secondary measures including reaction time, dexterity, mood, and depression.
Main Results:
- Increased Phe intake was noninferior to Phe restriction for working memory accuracy.
- No significant differences were observed in most secondary cognitive and mood outcomes.
- Sustained attention showed a statistically significant difference, and adverse events were more common with higher Phe intake.
Conclusions:
- A 4-week period of increased phenylalanine intake did not negatively impact working memory accuracy in early-treated adults with PKU.
- Further long-term studies are necessary to establish optimal phenylalanine management strategies throughout adulthood.
- The study registered under NCT03788343 provides insights into PKU adult dietary management.
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 stratification 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% confidence 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 significantly 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.
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