Does early treatment of PKU patients with sapropterin dihydrochloride affect brain development?
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ABSTRACT:
PROVIDER: PRJNA439302 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6871190.fastq.gz | Fastqsanger.gz | |||
| SRR6871200.fastq.gz | Fastqsanger.gz | |||
| SRR6871191.fastq.gz | Fastqsanger.gz | |||
| SRR6871201.fastq.gz | Fastqsanger.gz | |||
| SRR6871192.fastq.gz | Fastqsanger.gz |
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Project description:Background: Phenylketonuria (PKU) is an inborn error of metabolism caused by phenylalanine hydroxylase (PAH) deficiency. Patients with mild or moderate PKU can be successfully treated with sapropterin dihydrochloride (SD) which since recently is registered for usage from the age of 4 months. SD is a pharmaceutical version of tetrahydrobiopterin (BH4), a cofactor of PAH. Similar BH4 concentrations to those observed in plasma have been found in CSF of patients after a single oral administration thus proving that SD crosses the BBB. Hyperactivity has recently been reported as a post-marketing observation in some PKU patients treated with SD. Methods: 60 or 120 ng/ml sepiapterin, a stable precursor of BH4, were applied to study the effects of BH4 on developing brain cells in 3D organotypic rat brain cell cultures at two developmental stages. Immunohistochemistry, western blotting, metabolomics and RNA sequencing were performed. Findings: BH4 and BH2 measurements confirmed a successful conversion of sepiapterin to the active form BH4. In the earlier developmental stage, brain cell specific markers showed swollen astrocytes and diminished astrocytic fibres, delayed differentiation of oligodendrocytes and perturbation of axonal elongation. Immunofluorescence for activated caspase-3 revealed an increased apoptosis rate. We also found signs of perturbated GABAergic neurotransmission. RNAseq analyses revealed a number of significantly affected genes. GO enrichment allowed to identify key biological processes. Interestingly, none of these effects was observed in the later developmental stage. We show deleterious effects of SD on developing brain cells in a rat in vitro model. This observation raises the question whether the use of SD can be recommended in very young PKU patients as currently licensed.
2021-03-20 | GSE112108 | GEO
Project description:Streptomyces sp. PKU-EA00015 Genome sequencing and assembly
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Project description:Streptomyces sp. PKU-MA01144 Genome sequencing and assembly
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Project description:Dr. Wong's laboratory is interested in examining if and how the absence of prion protein expression could affect the cellular glycosylation enzymes during development. Prion protein is a glycoprotein and changes in glycosylation on the protein have been implicated in the pathogenic process. Our objective is to examine if and how the absence of prion protein expression could affect the cellular glycosylation enzymes during development. To do this, we proposed to compare and contrast the expression profile of the glycosylation enzymes in control and prion protein knockout mouse brain at the age of 2 and 82 weeks (n=3). RNA preparations from control and prion protein knockout mice brain of age ~2 and 82 weeks were sent to the Microarray Core (E). The RNA was amplified, labeled, and hybridized to GLYCOv3 microarrays.
2011-04-29 | E-GEOD-28935 | biostudies-arrayexpress
Project description:BACKGROUND:The implementation of neonatal screening and the early initiation of lifelong therapy have helped to prevent severe complications and enabled much more favorable outcomes for early-treated phenylketonuria (ETPKU) patients. However, PKU patients tend to develop subtle cognitive and psychosocial abnormalities and the strict dietary therapy can present financial and social burden. Thus, PKU is expected to affect the quality of life (QoL) of these patients. There is insufficient evidence regarding the relationship between metabolic control and Health-Related QoL (HRQoL). We aimed to assess the effect of short- and long-term therapy on QoL among Hungarian adult PKU patients using the standardized PKU-specific PKU-QoL questionnaire. Methods: We conducted a single-centre, cross-sectional, observational study in Hungary. We included adult PKU patients treated with diet and amino acid supplements only. Patients reported HRQoL using the standardized adult PKU-QoL questionnaire and mean blood Phe concentrations were assessed for three different time periods: the previous 10 years, the previous year and concentration at the time of completing the questionnaire. The correlation between patients' QoL scores and their Phe levels was assessed. The classical PKU group was further divided into "good" and "suboptimal" adherence groups based on individual mean Phe levels in the examined time period. We evaluated differences in QoL among the two subgroups of classical PKU patients. QoL scores between classical and non-classical patients were also compared. Results: Data from 88 adult patients were analysed (66 had classical PKU). No median PKU-QoL score reached major or severe impact/frequent symptoms in any domain. The highest scores (meaning larger burden) were mostly related to emotional impact of PKU and disease management. When performing correlation analysis between Phe levels and QoL scores by all patients we found weak to fair positive correlation in several domains either short or long term. Patients with classical PKU reported greater financial impact of PKU than patients with less severe PKU. Classical PKU patients with good therapy adherence tended to report better HRQoL scores than patients with suboptimal adherence. Conclusion: We conclude that patients showed good HRQoL using the PKU-specific questionnaire. Our study demonstrates that suboptimal metabolic control is negatively associated with patients' HRQoL.
| S-EPMC7183227 | biostudies-literature
Project description:To study developmental trajectories in brain organoids, we conducted scRNA-seq and scATAC-seq in parallel on a dense timecourse of early development.
2022-08-18 | E-MTAB-11998 | biostudies-arrayexpress
Project description:To study developmental trajectories in brain organoids, we conducted scRNA-seq and scATAC-seq in parallel on a dense timecourse of early development.
2022-08-18 | E-MTAB-12001 | biostudies-arrayexpress
Project description:BACKGROUND:According to studies of phenylketonuria (PKU), the Brazilian population's metabolic control shows unsatisfactory indexes from childhood. Research on patients' perceived difficulties or barriers to adherence to treatment can help us to comprehend how these outcomes are associated. The present study aimed to: (1) describe the development of an inventory for identifying the most frequent and relevant perceived barriers to PKU treatment from the perspective of patients, caregivers, and healthcare professionals; (2) evaluate certain psychometric characteristics of the new measure; and, (3) explore potential predictors (sociodemographic and medical characteristics) that may contribute to increasing the number of perceived barriers and examine whether the number of barriers is associated with the degree of adherence shown by the patient. RESULTS:Participants in the study were 23 patients with PKU (M age?=?18.0?years; SD?=?7.3; range 6 to 34?years; 69% early-treated) in classical (n?=?11) and mild (n?=?12) form, and 11 caregivers. The inventory, developed to ascertain perceived barriers to treatment, was completed by patients (? 13?years) and caregivers of patients aged 6 to 17?years. Analyses were conducted to investigate whether barrier inventory scores were associated with adherence to treatment as measured by phenylalanine levels in patients' medical records. Scores on the inventory differed across the patient age groups: adolescents had lower scores (i.e. reported fewer barriers) compared with those of adults (U?=?8.000, p?=?0.008); patients with better recent metabolic control also reported fewer perceived barriers than did patients with poor adherence (U?=?20.000, p?=?0.009); and the number of perceived barriers was positively associated with recent blood phenylalanine concentration (Kendall's taub?=?0.41; p?=?0.001). CONCLUSIONS:These results suggest that the inventory has merit in assessing perceived barriers and support the need for further research on barriers perceived by PKU patients.
| S-EPMC7195505 | biostudies-literature