Phenylketonuria (PKU)
Conditions
Keywords
saliva, genetics
Brief summary
The GENOPHEN study aims to explore the links between the genome, metabolomic profile, and clinical phenotype in adults with early-treated PKU.
Detailed description
• There is a wide clinical variability among PKU patients. Even siblings can present discrepancies regarding the phenotype. The reasons for that are not completely known. There are over 3,300 variants of the PAH gene, some of which influence the severity of the disease, but their impact in adulthood remains poorly understood. Other genes (SLC7A5, HULC, DNAJC12, SHANK family) could also modulate the phenotype. Working Hypotheses: * Some genetic variants influence the severity of neuropsychological and systemic disorders in adults with early-treated PKU. * Metabolomic analysis of sera will identify new biomarkers correlated with the severity of the disease. Methodology: * The study is based on the ECOPHEN cohort (187 adult PKU patients followed for 5 years), of which 150 will provide a DNA sample from saliva for whole-genome sequencing. * Genetic variants will be sought and correlated with clinical, biological, and neuropsychological data. * A non-targeted metabolomic analysis by LC-MS/MS will be performed on the sera, then the metabolic profiles will be associated with phenotypes and genotypes. Objectives and Expected Outcomes: * Better understand the heterogeneity of the disease in adulthood. * Identify associations between genetic variants, metabolic profiles, and clinical evolution. * Pave the way for personalized management and new therapeutic approaches for adult PKU patients.
Interventions
None listed
Sponsors
University Hospital, Tours
Study design
Observational model
CASE_ONLY
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* PKU patients over the age of 18, * diagnosed through the newborn screening program, * patients who participated in the final visit of the ECOPHEN study, * affiliation with a health insurance plan, * informed consent dated and signed by patients for DNA analysis (saliva sample)
Exclusion criteria
* Patients whose PKU diagnosis was not detected during neonatal screening, * Patients who have not signed a dated informed consent form, * Patients who are unable to provide a saliva sample.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Identification of metabolite clusters | Enrolment | untargeted metabolomic analysis of plasma samples collected during the ECOPHEN study Phenylalanine level (\> 900 µmol/L, 900-600 µmol/L, \< 600 µmol/L), response to BH4 (Complete response: decrease in Phe levels after treatment leading to normalization of Phe levels; partial response: 30% decrease without normalization; non-responder: decrease of less than 30% in Phe levels.) |
| Identification of genetic variants DNAJC12, HULC, SLC7A5, and SHANK and other ones | Enrolment | genome sequencing of DNA collected from saliva samples during the GENOPHEN study. The DNAJC12, HULC, SLC7A5, and SHANK (SHANK1, SHANK2, and SHANK3) variants will be listed and classified as frequent (allele frequency \> 1%) or rare (allele frequency \< 1%) according to the gnomAD database. The same will apply to other variants potentially identified by genome sequencing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of patients with neurological complications | Enrolment | — |
| average intelligence quotient (IQ) | Enrolment | WAIS IV results identified in the ECOPHEN cohort study (\>= 130 : Very superior; 120-129 Superior; 110-119 High average; 90-109 Average; 80-89 : Low average; 70-79 Borderline; =\< 69 Extremely low) |
| California Verbal Learning Test | Enrolment | CVLT results identified in the ECOPHEN cohort study. There is no minimum or maximum score; it is a "raw" score. |
| Trail Making Test | Enrolment | TMT results identified in the ECOPHEN cohort study. This is the number of seconds it takes to finish connecting the points on a "path" consisting of 25 points; the lower the number, the better (the patient is faster), but there isn't really a minimum and no maximum. |
| Beck Depression Inventory | Enrolment | BDI test results identified in the ECOPHEN cohort study The score ranges from 0 to 63, with the following qualitative interpretations: 0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; 29-63: severe depression |
| Weight changes | Time of enrollment | Body mass index (Kg/m2) |
| Bone mineral density changes | Enrolment | Bone mineral density, measured by DWA, expressed as Z-scores |
Countries
France
Contacts
CONTACTFrançois MAILLOT, Pr
PRINCIPAL_INVESTIGATORYannick MOUPATAM-NGAMBY-ADRIAASEN, Sir
University, Tours
Outcome results
None listed