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

NCT07220265 | Recruiting

• 2 other identifiers: 2092228R21HD115129-01A1
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Carrier of Phenylketonuria; Healthy

Outcome Measures

Primary Outcomes (8)

• Blood Phenylalanine Levels

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

• Brain Phenylalanine Levels

  Brain Phenylalanine Levels estimated using magnetic resonance spectroscopy (MRS)

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

• Brain Phenylalanine-to-Tyrosine Ratio

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

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

• Neural Activity during Go/No-Go Task

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

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

• Operational Span Task

  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.

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

• Multi-Source Interference Task

  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.

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

• Grooved Pegboard Test

  Performance-based measure of processing speed \& fine motor control

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

• Resting-State Functional Connectivity

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

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

Secondary Outcomes (9)

• Brain concentrations of glutamate, glutathione, creatine, and other metabolites

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

• PROMIS Anxiety - Short Form 8a

  Baseline only

• PROMIS Depression - Short Form 8a

  Baseline only

• PROMIS Sleep - Short Form 8a

  Baseline only

• PROMIS Fatigue - Short Form 8a

  Baseline only

Study Arms (2)

PKU Carriers

OTHER

Heterozygous carriers of a pathogenic variant of the PAH gene associated with phenylketonuria (PKU)

Dietary Supplement: Phenylalanine (Phe); Dietary Supplement: Placebo

Non-Carriers

OTHER

Individuals who do not carry a pathogenic variant of the PAH gene

Dietary Supplement: Phenylalanine (Phe); Dietary Supplement: Placebo

Interventions

Phenylalanine (Phe) DIETARY_SUPPLEMENT

Oral ingestion of phenylalanine (Phe)

Non-Carriers; PKU Carriers

Placebo DIETARY_SUPPLEMENT

Oral ingestion of Placebo (Vitamin C)

Non-Carriers; PKU Carriers

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• University of Missouri-Columbia: lead

Study Sites (1)

University of Missouri-Columbia

Columbia, Missouri, 65201, United States

RECRUITING

MeSH Terms

Interventions

Phenylalanine

Intervention Hierarchy (Ancestors)

Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential

Central Study Contacts

Shawn Christ

CONTACT

573-884-8140; christse@missouri.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Psychological Sciences

Study Record Dates

• First Submitted: October 20, 2025
• First Posted: October 23, 2025
• Study Start: December 19, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: March 11, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ANALYTIC CODE
• Time Frame: Data will be made available when the award ends (currently 04/30/2027)or when a publication is available, whichever comes first. As required by NDA, studies will also be created that contain the data used for every publication. Those studies will be shared when the pre-print is available. NDA will make decisions about how long to preserve the data, but that data archive has not deleted any deposited data up to now.
• Access Criteria: All data will be deposited to the NDA. To request access of the data, researchers will use the standard processes at NDA, and the NDA Data Access Committee will decide which requests to grant. The standard NDA data access process allows access for one year and is renewable.

Locations

US (1)