An observational study in Phenylketonuria, sponsored by Birmingham Women's and Children's NHS Foundation Trust. Recruiting at 1 site in United Kingdom. Open to participants aged 3 Years to 17 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-10-06.
Sponsored by Birmingham Women's and Children's NHS Foundation Trust · Observational
Phenylketonuria (PKU) is an inherited disorder of phenylalanine (Phe) metabolism. The mainstay of treatment is a Phe-restricted diet, which aims to maintain blood Phe concentrations within the recommended range and prevent neurological complications. Some individuals with PKU respond to pharmacological treatments, including sapropterin, a synthetic form of tetrahydrobiopterin (BH4), or sepiapterin. These treatments may increase Phe tolerance and allow a less restrictive diet.
Diet is an important determinant of gut microbiota composition and function. However, the effects of the Phe-restricted diet and pharmacologically enabled dietary relaxation on the gut microbiota in PKU remain poorly understood.
This observational study includes children and adolescents with PKU aged 3-17 years attending Birmingham Children's Hospital. Participants include those managed exclusively with a Phe-restricted diet, those receiving sapropterin, and those receiving sepiapterin. One healthy household control is recruited for each participant with PKU.
Faecal samples are collected for shotgun metagenomic sequencing and metabolite profiling. Dietary intake, gastrointestinal symptoms, stool characteristics, clinical information, and PKU treatment are also assessed.
The study investigates whether gut microbiota composition, microbial functional potential, and faecal metabolite profiles differ between participants managed with a Phe-restricted diet, those receiving pharmacological treatment, and healthy household controls. The findings may improve understanding of the relationships between PKU treatment, dietary restriction, gastrointestinal health, and the gut microbiome and may inform future nutritional strategies for individuals with PKU.
This is a single-centre, cross-sectional observational study conducted at Birmingham Children's Hospital. The study investigates the association between phenylketonuria (PKU) treatment, degree of dietary restriction, gastrointestinal health, and the composition and functional potential of the gut microbiota.
Children and adolescents aged 3-17 years with early-treated PKU are recruited into one of three cohorts according to their existing clinical management: treatment with a phenylalanine-restricted diet alone (anticipated n=30), treatment with sapropterin alongside an individualised phenylalanine-restricted diet (anticipated n=30), or treatment with sepiapterin alongside an individualised phenylalanine-restricted diet (anticipated n=14). Participants receiving sapropterin or sepiapterin have been receiving treatment for at least three months and have achieved at least a 100% increase in natural protein tolerance compared with their pre-treatment prescription. Treatment allocation, medication dosage, and dietary management are determined as part of routine clinical care and are not assigned or modified by the study.
One healthy household control is recruited for each participant with PKU. Household controls are aged 3 years or older and do not have PKU or another inherited metabolic disorder. Recruiting controls from the same household aims to reduce the influence of shared environmental factors, including living conditions and food availability, when comparing gut microbiota profiles. The anticipated total enrolment is 148 participants, comprising 74 participants with PKU and 74 household controls.
Each participant provides a single faecal sample. Samples are stored at -80°C and analysed using shotgun metagenomic sequencing to characterise microbial taxonomic composition, within-sample diversity, between-sample community differences, and microbial functional potential. Taxonomic profiles are assessed at multiple levels, including phylum, genus, and species. Functional annotation is used to characterise microbial genes, enzymes, and metabolic pathways.
Dietary intake is assessed using a 24-hour dietary recall, including natural protein intake, protein substitute intake, dietary fibre intake, and consumption of special low-protein foods. Gastrointestinal symptoms are assessed using the age-appropriate self-report or parent-proxy version of the PedsQL Gastrointestinal Symptoms Module, and stool form is assessed using the Bristol Stool Form Scale. Relevant demographic and clinical information, including age, sex, anthropometric measurements, PKU treatment, and metabolic control, is also collected.
The findings from this study may support the development of nutritional strategies and protein substitutes that more effectively promote gastrointestinal and metabolic health in individuals with PKU.
191 studies on the registry are indexed under Phenylketonurias; 40 are open to participants now.
This study's planned enrollment of 148 is above the median of 37 across 61 observational studies indexed under Phenylketonurias.
Browse Phenylketonurias studies →Birmingham Women's and Children's NHS Foundation Trust is the lead sponsor of 17 studies on the registry; 5 are open to participants now.
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Children and adolescents aged 3-17 years with early-treated phenylketonuria receiving clinical care at Birmingham Children's Hospital are recruited into one of three cohorts according to their current treatment: a phenylalanine-restricted diet alone, sapropterin, or sepiapterin.
One healthy household control aged 3 years or older, without phenylketonuria or another inherited metabolic disorder, is recruited for each participant with phenylketonuria. All participants are enrolled according to predefined eligibility criteria.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Participants with PKU:
Healthy household controls:
Exclusion Criteria:
Children and adolescents aged 3-17 years with early-treated phenylketonuria who are managed exclusively with a phenylalanine-restricted diet and are not receiving sapropterin or sepiapterin. Participants provide a faecal sample and undergo dietary, clinical, gastrointestinal symptom, and stool assessments.
Other: Phenylalanine-restricted diet alone
Children and adolescents aged 3-17 years with early-treated phenylketonuria who have been receiving sapropterin for at least 3 months and have achieved at least a 100% increase in natural protein tolerance compared with before treatment. Sapropterin treatment is not assigned as part of this observational study. Participants provide a faecal sample and undergo dietary, clinical, gastrointestinal symptom, and stool assessments.
Drug: Sapropterin Dihydrochloride
Children and adolescents aged 3-17 years with early-treated phenylketonuria who have been receiving sepiapterin for at least 3 months and have achieved at least a 100% increase in natural protein tolerance compared with before treatment. Sepiapterin treatment is not assigned as part of this observational study. Participants provide a faecal sample and undergo dietary, clinical, gastrointestinal symptom, and stool assessments.
Drug: Sepiapterin
Healthy household members without phenylketonuria who are recruited at a ratio of one control for each participant with phenylketonuria. Controls provide a faecal sample and complete the relevant dietary, gastrointestinal symptom, and stool assessments.
Participants are managed with a phenylalanine-restricted diet and prescribed protein substitutes as part of their usual clinical care. They are not receiving sapropterin or sepiapterin. Dietary treatment is not assigned or modified by this observational study.
Participants receive sapropterin as part of their usual clinical care, alongside an individualised phenylalanine-restricted diet. Sapropterin treatment and dosage are prescribed independently of this observational study and are not assigned or modified by the investigators.
Also known as: Kuvan
Participants receive sepiapterin as part of their existing clinical management, alongside an individualised phenylalanine-restricted diet. Sepiapterin treatment and dosage are determined independently of this observational study and are not assigned or modified by the investigators.
Also known as: Sephience
Faecal gut microbiota taxonomic composition assessed by shotgun metagenomic sequencing
Taxonomic profiles, expressed as the relative abundance of microbial taxa at phylum, genus, and species levels, are derived from shotgun metagenomic sequencing of one faecal sample per participant. Profiles are compared among participants with PKU managed by a phenylalanine-restricted diet alone, sapropterin, or sepiapterin and healthy household controls.
Time frame: At enrolment (single faecal sample collection)
Faecal gut microbiota alpha diversity assessed by shotgun metagenomic sequencing
Within-sample microbial diversity is assessed from shotgun metagenomic sequencing data using alpha-diversity indices, including Shannon, Simpson, Chao1, ACE, and observed species. Alpha-diversity measures are compared across the study cohorts.
Time frame: At enrolment, based on a single faecal sample
Faecal gut microbiota beta diversity assessed by shotgun metagenomic sequencing
Differences in overall microbial community composition between participants are assessed using beta-diversity measures derived from shotgun metagenomic sequencing data, including Bray-Curtis dissimilarity. Microbial community profiles are compared across the study cohorts.
Time frame: At enrolment, based on a single faecal sample
Microbial functional potential assessed by shotgun metagenomic sequencing
Microbial genes and functional pathways are characterised from shotgun metagenomic sequencing data using functional annotation databases. The relative abundance of microbial genes, enzymes, and metabolic pathways is compared across the study cohorts.
Time frame: At enrolment, based on a single faecal sample
Gastrointestinal symptom burden assessed using the Pediatric Quality of Life Inventory™ 3.0 Gastrointestinal Symptoms Module
Gastrointestinal symptoms are assessed using the age-appropriate version of the Pediatric Quality of Life Inventory™ 3.0 Gastrointestinal Symptoms Module. The Gastrointestinal Symptoms Total Score and individual symptom-domain scores range from 0 to 100. Higher scores indicate fewer gastrointestinal symptoms and a better outcome, whereas lower scores indicate a greater gastrointestinal symptom burden and a worse outcome. Scores are compared across the study cohorts.
Time frame: At enrolment, based on a single faecal sample
Stool form assessed using the Bristol Stool Form Scale
Stool form of the collected faecal sample is classified using the Bristol Stool Form Scale, which ranges from type 1 (separate hard lumps) to type 7 (entirely liquid stool). Higher scores indicate progressively softer and looser stools; they do not inherently represent a better or worse outcome. Stool-form distributions are compared across the study cohorts.
Time frame: At enrolment, based on a single faecal sample
Dietary intake assessed using a 24-hour dietary recall
Dietary intake is assessed using a 24-hour dietary recall. Nutrient and food-group measures, including natural protein intake, protein substitute intake, dietary fibre intake, and consumption of special low-protein foods, are estimated and compared across the study cohorts.
Time frame: At enrolment, based on a single faecal sample
Plan to share: No — There is no current plan to share individual participant data because the study involves a small population with a rare condition, which may increase the risk of participant identification. Any future data sharing would be subject to participant consent, ethical and institutional approvals, and an appropriate data-sharing agreement. Aggregated study results will be disseminated through scientific publications and presentations.
No publications or documents are linked to this record.
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
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Birmingham Women's and Children's NHS Foundation Trust