Phenylketonuria
Conditions
Brief summary
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.
Detailed description
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.
Interventions
OTHERPhenylalanine-restricted diet alone
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.
DRUGSepiapterin
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.
Sponsors
Birmingham Women's and Children's NHS Foundation Trust
Universidade Nova de Lisboa
Study design
Observational model
COHORT
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
3 Years to 17 Years
Healthy volunteers
Yes
Inclusion criteria
Participants with PKU: * Aged 3-17 years. * Confirmed diagnosis of phenylketonuria following newborn screening. * Receiving ongoing clinical management for PKU. * For the diet-only cohort: managed with standard phenylalanine-restricted dietary treatment and not receiving sapropterin or sepiapterin. * For the sapropterin cohort: receiving sapropterin for at least three consecutive months and having achieved at least a 100% increase in natural protein tolerance compared with the pre-treatment prescription. * For the sepiapterin cohort: receiving sepiapterin for at least three consecutive months and having achieved at least a 100% increase in natural protein tolerance compared with the pre-treatment prescription. Healthy household controls: * Aged 3 years or older. * Living in the same household as a participating child or adolescent with PKU. * No known diagnosis of PKU or another inherited metabolic disorder.
Exclusion criteria
* Congenital malformations. * Chronic gastrointestinal disease. * Endocrine, liver, or kidney disease. * Other chronic medical conditions likely to affect gut microbiota composition. * Following a therapeutic diet for a medical condition other than PKU within the six months before stool sample collection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Faecal gut microbiota taxonomic composition assessed by shotgun metagenomic sequencing | At enrolment (single faecal sample collection) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Faecal gut microbiota alpha diversity assessed by shotgun metagenomic sequencing | At enrolment, based on a single faecal sample | 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. |
| Faecal gut microbiota beta diversity assessed by shotgun metagenomic sequencing | At enrolment, based on a single faecal sample | 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. |
| Microbial functional potential assessed by shotgun metagenomic sequencing | At enrolment, based on a single faecal sample | 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. |
| Gastrointestinal symptom burden assessed using the PedsQL Gastrointestinal Symptoms Module | At enrolment, based on a single faecal sample | Gastrointestinal symptoms are assessed using the age-appropriate self-report or parent-proxy version of the PedsQL Gastrointestinal Symptoms Module. Total and individual symptom-domain scores are calculated, with lower scores indicating a greater gastrointestinal symptom burden, and compared across the study cohorts. |
| Stool form assessed using the Bristol Stool Form Scale | At enrolment, based on a single faecal sample | Usual stool form is classified using the Bristol Stool Form Scale, ranging from type 1, representing separate hard lumps, to type 7, representing entirely liquid stool. Stool-form distributions are compared across the study cohorts. |
| Dietary intake assessed using a 24-hour dietary recall | At enrolment, based on a single faecal sample | 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. |
Countries
United Kingdom
Contacts
CONTACTAnita MacDonald, PhD
CONTACTCatarina Rodrigues, MSc
PRINCIPAL_INVESTIGATORAnita MacDonald, PhD
Birmingham Children's Hospital
Outcome results
None listed