Relationships Between the Genome and Metabolomic and Phenomic Signatures in Adult Patients With Early-Treated Phenylketonuria: a Multicenter Cross-sectional Study
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 149
- 试验地点
- 15
- 主要终点
- Identification of metabolite clusters
研究概览
简要总结
The GENOPHEN study aims to explore the links between the genome, metabolomic profile, and clinical phenotype in adults with early-treated PKU.
详细描述
• 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.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Only
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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.
结局指标
主要结局
Identification of metabolite clusters
时间窗: 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
时间窗: 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.
次要结局
- Number of patients with neurological complications(Enrolment)
- neurological complications(Enrolment)
- average intelligence quotient (IQ)(Enrolment)
- California Verbal Learning Test(Enrolment)
- Trail Making Test(Enrolment)
- Beck Depression Inventory(Enrolment)
- Weight changes(Time of enrollment)
- Bone mineral density changes(Enrolment)