Understanding how phenylketonuria affects the brain, heart, metabolism, and gut from childhood to adulthood
| ISRCTN | ISRCTN12620764 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN12620764 |
| Secondary identifying numbers | 18/C/2020 |
- Submission date
- 03/06/2025
- Registration date
- 16/07/2025
- Last edited
- 15/07/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nutritional, Metabolic, Endocrine
Plain English summary of protocol
Background and study aims
Phenylketonuria (PKU) is a common inherited condition where the body cannot properly break down an amino acid called phenylalanine. This happens because of a missing enzyme, which leads to harmful conditions. PKU mainly affects the brain, but secondary effects may involve the heart and alternative tissues. Current treatments include a special low-protein diet and medication, but not everyone responds well. This study aims to better understand the effects of PKU on the brain and heart, and how differences in gut bacteria and metabolism may affect symptoms and treatment success.
Who can participate?
The study will include people diagnosed with PKU or a related condition called hyperphenylalaninemia, including both children and adults living in Catalonia.
What does the study involve?
Participants will undergo tests using the latest technology to assess brain function and heart health. Researchers will also analyze participants’ gut bacteria, metabolic and bioenergetic profiles to see how these relate to their symptoms and treatment responses.
What are the possible benefits and risks of participating?
Taking part may give participants more detailed information about their health and could help improve future treatments. The tests involve some time and effort but do not carry significant risks.
Where is the study run from?
Fundació La Marató de TV3 in Catalonia (Spain)
When is the study starting and how long is it expected to run for?
December 2019 to March 2025
Who is funding the study?
Fundació La Marató de TV3 (Spain)
Who is the main contact?
garrabou@clinic.cat
Contact information
Public, Scientific, Principal Investigator
Casanova. 143
Barcelona
08036
Spain
 ORCID ID |
0000-0001-8973-9933 |
|---|---|
| Phone | +34 (0)93 227 54 00 - 2907 |
| garrabou@clinic.cat |
Study information
| Study design | Multicenter observational case-control study |
|---|---|
| Primary study design | Observational |
| Secondary study design | Case-control study |
| Study setting(s) | Hospital, Laboratory |
| Study type | Prevention |
| Scientific title | Phenylketonuria: from childhood to adults through brain functional connectomics, cardiovascular changes, metabolomic and intestinal microbiota characteristics |
| Study acronym | PKU.CAT |
| Study objectives | We propose the present study in order to progress in the knowledge of phenylketonuria (PKU), and we hypothesize that, in patients with PKU, compared with a control population of the same age and sex of our cultural and genetic environment: 1. The specific neuropsychological alterations of patients with PKU correlate with the structural and functional connectivity patterns observed in MRI, and with the metabolic control of the disease (diet adherence and Phe concentrations). 2. The metabolic and cardiovascular risk of these patients is largely explained by the higher prevalence of obesity, insulin resistance, diabetes, and arterial hypertension, factors that, in turn, are related to the metabolic control of the disease: adherence to the PKU diet and Phe concentrations. In turn, the in-depth characterization of the cardiovascular risk phenotype will allow the establishment of standardized recommendations to define specific prevention strategies for this group of patients at high cardiovascular risk. 3. The intestinal microbiota diversity profile and the metabolic products generated by it (metabolomics) are characteristic in this population and explain part of the neuropsychological, cardiometabolic phenotypic variability and of both dietary and tetrahydrobiopterin therapeutic response (BH4). |
| Ethics approval(s) |
Approved 18/06/2018, Hospital Clinic de Barcelona (Villaroel, 170, Barcelona, 08036, Spain; +34 93 227 54 00 - 1437; proceic@clinic.cat), ref: HCB/2020/0552 |
| Health condition(s) or problem(s) studied | Phenylketonuria |
| Intervention | Multicenter observational and controlled study for the cross-sectional analysis of both patients and age/sex-paired controls, either of pediatric and adult age. In the case of adult PKU patients, those with poor metabolic control were longitudinally followed up before and after a dietary or pharmacological therapeutic intervention. |
| Intervention type | Other |
| Primary outcome measure | 1. Neurological impairment measured using neuropsychological tests (Behavior Rating Inventory of Executive Function for Adults (BRIEF-A), Arithmetic subtest, Vocabulary subtests from the Wechsler Adult Intelligence Scale – IV edition (WAIS-IV)) at baseline, 36 months 2. Cardiovascular risk measured using carotid ultrasound, electrocardiography, continuous blood pressure monitoring, Oral Glucose Tolerance Test (OGTT) at baseline, 36 months |
| Secondary outcome measures | 1. Microbiota diversity is measured using stool sample analysis at baseline and 36 months 2. Individual metabolomic profiles are measured using blood and urine sample analysis at baseline and 36 months 3. Mitoquines and oxidative stress levels are measured using ELISA (GDF15, Humanin) and colorimetric assays (TBARS, 8-OHdG, TAC) at baseline and 36 months 4. Nutritional status is measured using clinical nutritional assessment, dietary intake record, and body composition analysis (DEXA) at baseline and 36 months 5. Liver morphology and elasticity are measured using liver ultrasound and elastography at baseline and 36 months 6. Physical activity levels are measured using the International Physical Activity Questionnaire (IPAQ) at baseline and 36 months 7. Dietary intake patterns are measured using the Food Frequency Questionnaire (FFQ-143) at baseline and 36 months 8. Cardiovascular health is measured using electrocardiography and ambulatory blood pressure monitoring (ABPM) at baseline and 36 months 9. Brain structure and function are measured using brain magnetic resonance imaging (MRI) at baseline and 36 months |
| Overall study start date | 17/12/2019 |
| Completion date | 10/03/2025 |
Eligibility
| Participant type(s) | Healthy volunteer, Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 2 Years |
| Upper age limit | 98 Years |
| Sex | Both |
| Target number of participants | 130 |
| Total final enrolment | 127 |
| Key inclusion criteria | Pediatric (<18 years old) and adult patients (≥18 years old) with a genetic diagnosis of PKU or hyperphenylalaninemia (PKU group) |
| Key exclusion criteria | 1. Intelligence quotient below 70 according to the WAIS/WISC tests 2. Pregnancy or planning a pregnancy during the study period 3. Active cancer 4. Severe chronic hepatic disease 5. Acute cardiovascular event in the 6 months prior to study inclusion 6. Common MRI contraindications 7. Creatinine levels ≥2.0 mg/dL |
| Date of first enrolment | 01/06/2020 |
| Date of final enrolment | 31/12/2024 |
Locations
Countries of recruitment
- Spain
Study participating centre
Barcelona
08036
Spain
Sponsor information
Charity
Carrer de la TV3, s/n
Sant Joan Despí
08970
Spain
| Phone | +34 (0)934 99 93 33 |
|---|---|
| fundaciomaratotv3@ccma.cat | |
| Website | http://www.tv3.cat/marato |
Funders
Funder type
Charity
Government organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- TV3 Marathon Foundation, Marathon Foundation, Fundació la Marató
- Location
- Spain
Results and Publications
| Intention to publish date | |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Stored in publicly available repository |
| Publication and dissemination plan | For dissemination of the project results, the following channels may be available: 1. Indexed journals: At least three original articles will be published in first quartile journals. Written by researchers in reference journals in the field of congenital metabolic diseases, neurology, neuroimaging, metabolism, cardiovascular risk, microbiology, etc (Journal of Inherited Metabolic Disease, Neuroimage). The selection will be adapted to the maximum possible impact based on the results obtained, with the objective of disseminating the results and generating synergies that allow revalidating and applying these results both in clinical practice and in future projects 2. Scientific conferences: Multiple oral and written communications, will be sent to the main national and international scientific conferences about congenital metabolism errors (Spanish Association of Congenital Metabolism Errors (AECOM), Society for the study of inborn errors of Metabolism (SSIEM), where the results obtained will be presented, the therapeutic recommendations extracted, as well as inciting to continue and revalidate the most outstanding findings Minority Disease Meetings under the auspices of SEMI and the Catalan Society of Minority Diseases 3. The most outstanding results that may be of interest to society will be disseminated through communications on the web portals (Hospital Clinic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona and Hospital San Juan de Dios) and in social networks (Twitter, Facebook, LinkedIn and Instagram). Publications are made in three languages (Catalan, Spanish and English) 4. Diffusion to the state media: Of the most outstanding results that may be of interest to the public. Press conferences will be organised and press releases will be sent to the media 5. Scientific dissemination actions among PKU patients through annual meetings with the association of patients and family members 6. Outreach actions at events such as "Minority Disease Day", science week, thematic weeks |
| IPD sharing plan | The study results (raw datasets) will be published in open-source data registries (i.e. Ensembl) and derived findings/conclusions in open-science journals aligned to DORA and Co-ARA guidelines |
Editorial Notes
14/07/2025: Trial's existence confirmed by Hospital Clinic de Barcelona.
