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NCT Number: NCT07220265

Impact of Phenylalanine Elevations on Brain and Cognition in Adult PKU Carriers

The goal of this clinical trial is to advance our understanding of the cognitive and neurophysiologic sequelae associated with suboptimal phenylalanine (Phe) metabolism in heterozygous carriers of phenylketonuria (PKU). The main questions it aims to answer are:

* Do PKU carriers experience prolonged elevations in brain Phe levels following oral ingestion of dietary Phe? * Do PKU carriers experience disruptions in cognitive functioning following oral ingestion of dietary Phe? * Do PKU carriers experience atypical brain activity following oral ingestion of dietary Phe? Researchers will compare PKU carriers and non-carriers following oral ingestion of dietary Phe and a placebo.

Participants will:

* Consume Phe or a placebo at two separate visits to our facility * At each visit, they will complete a series of MRIs and cognitive tests throughout the day

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Key information

Conditions

Carrier of Phenylketonuria Healthy

Age range

18 year–60 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

University of Missouri-Columbia

Columbia, Missouri, 65201, United States

Location status: Recruiting

Location contact

Shawn Christ

CONTACT

[email protected]

573-884-8140

About this study

Limitations inherent in past studies of phenylketonuria (PKU) carriers (e.g., poor genetic characterization of sample resulting in inclusion of homozygous non-PKU relatives, reliance on rudimentary or overly broad behavioral assessment tools) make it difficult to conclude the extent to which neurophysiologic and cognitive processes are affected in these individuals. To address this gap in the literature, we propose to conduct a double-blind crossover study in a sample of genetically-confirmed sample of 18 heterozygous PKU carriers and 18 non-carriers. A principled investigation of the effects of elevated phenylalanine (Phe) on neurocognition will involve participants performing an fMRI n-back WM task, resting state scan, and a battery of select cognitive tests at 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo. Blood and brain levels of Phe and Tyr will also be assessed at each timepoint.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Age 18-60 years
  • For the PKU carrier group: Individuals who are the parent of an individual with PKU or who are otherwise have confirmed PKU carrier status (e.g., a sibling of someone with PKU who has had genetic testing done)
  • For the non-carrier group: Individuals who do not have PKU or a family history of PKU

Exclusion criteria

  • Obesity as defined by a body mass index (BMI) over 30*
  • Taking oral contraceptives on the day of testing session*
  • Positive cotinine urine test showing nicotine use
  • History of major neurologic condition (e.g., multiple sclerosis, severe closed head injury, Parkinson's disease)) unrelated to PKU and known to adversely impact brain health and function
  • Contraindications for safe MRI participation such as (a) pregnancy or plans to become pregnant during period of study enrollment; or (b) metallic objects inside the body (e.g., surgical staples left in the body following surgery, middle ear prosthesis, metal foreign objects lodged inside the eye, heart pacemakers).

Treatment and study plan

Phenylalanine (Phe)

Dietary Supplement

Oral ingestion of phenylalanine (Phe)

Placebo

Dietary Supplement

Oral ingestion of Placebo (Vitamin C)

Primary outcomes

  1. Blood Phenylalanine Levels

    Time frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo

  2. Brain Phenylalanine Levels

    Time frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo

    Brain Phenylalanine Levels estimated using magnetic resonance spectroscopy (MRS)

  3. Brain Phenylalanine-to-Tyrosine Ratio

    Time frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo

    Ratio of Phenylalanine-to-Tyrosine concentrations in the brain as estimated using magnetic resonance spectroscopy (MRS)

  4. Neural Activity during Go/No-Go Task

    Time frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo

    Pattern of brain activation as captured using functional MRI while performing a go/no-go inhibitory task

  5. Operational Span Task

    Time frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo

    Performance-based measure of working memory ability. In this task, participants first solve a math problem and then see a letter, and then solve another math problem, and see another letter. This math-letter sequence is repeated from three to seven times for each trial with an unpredictable length each time. After each math-letter sequence, participants are asked to recall, in order, the preceding letters. Scores are calculated by summing the number of letters correctly recalled in the correct order.

  6. Multi-Source Interference Task

    Time frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo

    Performance-based measure of focused attention. ). In this task, participants are shown a display containing three horizontally-aligned numbers (i.e., 1, 2, or 3) and asked to respond as quickly as possible to the location (position #1, 2, or 3) of the number stimulus that is different from the others. The location may be congruent (e.g., "323") or incongruent (e.g., "112") with identity of the target number. Mean response time and error rate will served as the outcome variables.

  7. Grooved Pegboard Test

    Time frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo

    Performance-based measure of processing speed & fine motor control

  8. Resting-State Functional Connectivity

    Time frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo

    Synchronization of neural activity within brain networks as measured by functional MRI while participants are at rest

Secondary outcomes

  1. Brain concentrations of glutamate, glutathione, creatine, and other metabolites

    Time frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo

    Concentrations of various brain metabolites as estimated using magnetic resonance spectroscopy (MRS)

  2. PROMIS Anxiety - Short Form 8a

    Time frame: Baseline only

    A patient-reported outcome (PRO) measure assessing symptoms of anxiety. Scores range from 8 to 40, with higher scores indicating more/worse symptoms.

  3. PROMIS Depression - Short Form 8a

    Time frame: Baseline only

    A patient-reported outcome (PRO) measure assessing symptoms of depression. Scores range from 8 to 40, with higher scores indicating more/worse symptoms.

  4. PROMIS Sleep - Short Form 8a

    Time frame: Baseline only

    A patient-reported outcome (PRO) measure assessing symptoms of sleep disturbance. Scores range from 8 to 40, with higher scores indicating more/worse symptoms.

  5. PROMIS Fatigue - Short Form 8a

    Time frame: Baseline only

    A patient-reported outcome (PRO) measure assessing symptoms of fatigue. Scores range from 8 to 40, with higher scores indicating more/worse symptoms.

  6. PROMIS Cognitive Function - Short Form 8a

    Time frame: Baseline only

    A patient-reported outcome (PRO) measure assessing symptoms of cognitive dysfunction. Scores range from 8 to 40, with higher scores indicating more/worse symptoms.

  7. • Executive Function, Attention, and Speed Symptom Inventory (EASSI)

    Time frame: Baseline only

    Patient-reported outcome (PRO) measure of everyday symptoms of cognitive dysfunction. Scores range from 72 to 360, with higher scores indicating more/worse symptoms.

  8. Adult ADHD Self-Report Scale (ASRS)

    Time frame: Baseline only

    Patient-reported outcome (PRO) measure of ADHD symptoms. Scores range from 0 to 124, with higher scores indicating more/worse symptoms.

  9. Matrix Reasoning subtest from the WASI-2

    Time frame: Baseline only

    Performance-based measure of fluid intelligence

Study contacts

Contact information is provided by the study sponsor or research team.

Shawn Christ

CONTACT

[email protected]

573-884-8140

Sponsors and collaborators

Lead sponsor

University of Missouri-Columbia

Other

Collaborators

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Registry information

Official study title

The Impact of Phenylalanine Elevations on Metabolic, Cognitive, and Neural Functioning in Adults Heterozygous for Phenylketonuria (PKU)

Important dates

Study start
2025
Primary completion
2026
Study completion
2026
First posted
Oct 23, 2025
Registry last updated
Mar 11, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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