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The Western Journal of Medicine Oct 1979
Topics: Humans; Infant, Newborn; Isoenzymes; Liver; Phenylalanine Hydroxylase; Phenylketonurias
PubMed: 506223
DOI: No ID Found -
Postgraduate Medical Journal Jul 1970The development of a practical screening procedure for phenylketonuria and the improvement in methods of chemical analysis have led to a realization that Folling's... (Review)
Review
The development of a practical screening procedure for phenylketonuria and the improvement in methods of chemical analysis have led to a realization that Folling's (1934) disease of phenylketonuria is not a single entity. In this commentary, the current view on some aspects of phenylketonuria will be reviewed and the problems illustrated by experience gained in the Phenylketonuria Clinic at the Royal Alexandra Hospital for Children in Sydney, at present attended by fifty-six children. From April 1964, fifty-six infants and children were referred because of a positive screening test. Six were no longer abnormal at the time of retesting, forty-two had classical phenylketonuria and eight showed an atypical pattern. Subsequent family studies revealed five other classical phenylketonuric children, all of whom were retarded, and one other atypical phenylketonuric boy.
Topics: Amino Acid Metabolism, Inborn Errors; Child; Child, Preschool; Congenital Abnormalities; Diet Therapy; Female; Humans; Infant; Infant Nutritional Physiological Phenomena; Infant, Newborn; Intellectual Disability; Mass Screening; Minerals; Phenylalanine; Phenylketonurias; Pregnancy; Pregnancy Complications; Time Factors; Transaminases; Vitamins
PubMed: 4920277
DOI: 10.1136/pgmj.46.537.430 -
The Cochrane Database of Systematic... Mar 2015Phenylketonuria results from a deficiency of the enzyme phenylalanine hydroxylase. Dietary restriction of phenylalanine keeps blood phenylalanine concentration low. Most... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Phenylketonuria results from a deficiency of the enzyme phenylalanine hydroxylase. Dietary restriction of phenylalanine keeps blood phenylalanine concentration low. Most natural foods are excluded from diet and supplements are used to supply other nutrients. Recent publications report a decrease in blood phenylalanine concentration in some patients treated with sapropterin dihydrochloride. We examined the evidence for the use of sapropterin dihydrochloride to treat phenylketonuria. This is an update of a previously published Cochrane Review.
OBJECTIVES
To assess the safety and efficacy of sapropterin dihydrochloride in lowering blood phenylalanine concentration in people with phenylketonuria.
SEARCH METHODS
We identified relevant trials from the Group's Inborn Errors of Metabolism Trials Register. Date of last search: 11 August 2014.We also searched ClinicalTrials.gov and Current controlled trials. Last search: 4 September 2014We contacted the manufacturers of the drug (BioMarin Pharmaceutical Inc.) for information regarding any unpublished trials.
SELECTION CRITERIA
Randomized controlled trials comparing sapropterin with no supplementation or placebo in people with phenylketonuria due to phenylalanine hydroxylase deficiency.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed trials and extracted outcome data.
MAIN RESULTS
Two placebo-controlled trials were included. One trial administered 10 mg/kg/day sapropterin in 89 children and adults with phenylketonuria whose diets were not restricted and who had previously responded to saproterin.This trial measured change in blood phenylalanine concentration. The second trial screened 90 children (4 to 12 years) with phenylketonuria whose diet was restricted, for responsiveness to sapropterin. Forty-six responders entered the placebo-controlled part of the trial and received 20 mg/kg/day sapropterin. This trial measured change in both phenylalanine concentration and protein tolerance. Both trials reported adverse events. The trials showed an overall low risk of bias; but both are Biomarin-sponsored. One trial showed a significant lowering in blood phenylalanine concentration in the sapropterin group (10 mg/kg/day), mean difference -238.80 μmol/L (95% confidence interval -343.09 to -134.51); a second trial (20 mg/kg/day sapropterin) showed a non-significant difference, mean difference -51.90 μmol/L (95% confidence interval -197.27 to 93.47). The second trial also reported a significant increase in phenylalanine tolerance, mean difference18.00 mg/kg/day (95% confidence interval 12.28 to 23.72) in the 20 mg/kg/day sapropterin group.
AUTHORS' CONCLUSIONS
There is evidence of short-term benefit from using sapropterin in some people with sapropterin-responsive forms of phenylketonuria; blood phenylalanine concentration is lowered and protein tolerance increased. There are no serious adverse events associated with using sapropterin in the short term.There is no evidence on the long-term effects of sapropterin and no clear evidence of effectiveness in severe phenylketonuria.
Topics: Adult; Biopterins; Child; Child, Preschool; Humans; Phenylalanine; Phenylketonurias; Randomized Controlled Trials as Topic
PubMed: 25812600
DOI: 10.1002/14651858.CD008005.pub4 -
Journal of Cellular and Molecular... Sep 2023To date more than 1000 different variants in the PAH gene have been identified in patients with phenylketonuria (PKU). In Iran, several studies have been performed to... (Review)
Review
To date more than 1000 different variants in the PAH gene have been identified in patients with phenylketonuria (PKU). In Iran, several studies have been performed to investigate the genetics bases of the PKU in different parts of the country. In this study, we have analysed and present an update of the mutational landscape of the PAH gene as well as the population genetics and frequencies of detected variants for each cohort. Published articles on PKU mutations in Iran were identified through a comprehensive PubMed, Google Scholar, Web of Science (ISI), SCOPUS, Elsevier, Wiley Online Library and SID literature search using the terms: "phenylketonuria", "hyperphenylalaninemia", and "PKU" in combination with "Iran", "Iranian population", "mutation analysis", and "Molecular genetics". Among the literature-related to genetics of PKU, 18 studies were on the PKU mutations. According to these studies, in different populations of Iran 1497 patients were included for mutation detection that resulted in detection of 129 different mutations. Results of genetic analysis of the different cohorts of Iranian PKU patients show that the most prevalent mutation in Iran is the pathogenic splice variant c.1066-11G > A, occurring in 19.54% of alleles in the cohort. Four other common mutations were p.Arg261Gln, p.Pro281Leu, c.168 + 5G > C and p.Arg243Ter (8.18%, 6.45%, 5.88% and 3.7%, respectively). One notable feature of the studied populations is its high rate of consanguineous marriages. Considering this feature, determining the prevalent PKU mutations could be advantageous for designing screening and diagnostic panels in Iran.
Topics: Humans; Phenylalanine Hydroxylase; Iran; Gene Frequency; Phenylketonurias; Mutation; Genotype; DNA Mutational Analysis
PubMed: 37525467
DOI: 10.1111/jcmm.17865 -
The Cochrane Database of Systematic... Jul 2020Phenylketonuria is an inherited disease treated with dietary restriction of the amino acid phenylalanine. The diet is initiated in the neonatal period to prevent... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Phenylketonuria is an inherited disease treated with dietary restriction of the amino acid phenylalanine. The diet is initiated in the neonatal period to prevent learning disability; however, it is restrictive and can be difficult to follow. Whether the diet can be relaxed or discontinued during adolescence or should be continued for life remains a controversial issue, which we aim to address in this review. This is an updated version of a previously published review.
OBJECTIVES
To assess the effects of a low-phenylalanine diet commenced early in life for people with phenylketonuria. To assess the possible effects of relaxation or termination of the diet on intelligence, neuropsychological outcomes and mortality, growth, nutritional status, eating behaviour and quality of life.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Most recent search of the Inborn Errors of Metabolism Trials Register: 30 April 2020.
SELECTION CRITERIA
All randomised or quasi-randomised controlled trials comparing a low-phenylalanine diet to relaxation or termination of dietary restrictions in people with phenylketonuria.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed study eligibility and methodological quality, and subsequently extracted the data.
MAIN RESULTS
We included four studies in this review (251 participants), and found few significant differences between treatment and comparison groups for the outcomes of interest. Blood phenylalanine levels were significantly lower in participants with phenylketonuria following a low-phenylalanine diet compared to those on a less restricted diet, mean difference (MD) at three months -698.67 (95% confidence interval (CI) -869.44 to -527.89). Intelligence quotient was significantly higher in participants who continued the diet than in those who stopped the diet, MD after 12 months 5.00 (95% CI 0.40 to 9.60). However, these results came from a single study.
AUTHORS' CONCLUSIONS
The results of non-randomised studies have concluded that a low-phenylalanine diet is effective in reducing blood phenylalanine levels and improving intelligence quotient and neuropsychological outcomes. We were unable to find any randomised controlled studies that have assessed the effect of a low-phenylalanine diet versus no diet from diagnosis. In view of evidence from non-randomised studies, such a study would be unethical and it is recommended that low-phenylalanine diet should be commenced at the time of diagnosis. There is uncertainty about the precise level of phenylalanine restriction and when, if ever, the diet should be relaxed. This should be addressed by randomised controlled studies; however, no new studies are expected in this area so we do not plan to update this review.
Topics: Child, Preschool; Humans; Intelligence; Phenylalanine; Phenylketonurias; Randomized Controlled Trials as Topic; Treatment Outcome; Withholding Treatment
PubMed: 32672365
DOI: 10.1002/14651858.CD001304.pub3 -
Nutrients Feb 2021Protein substitutes developed for phenylketonuria (PKU) are a synthetic source of protein commonly based on L-amino acids. They are essential in the treatment of... (Review)
Review
Protein substitutes developed for phenylketonuria (PKU) are a synthetic source of protein commonly based on L-amino acids. They are essential in the treatment of phenylketonuria (PKU) and other amino acid disorders, allowing the antagonistic amino acid to be removed but with the safe provision of all other amino acids necessary for maintaining normal physiological function. They were first formulated by a chemist and used experimentally on a 2-year-old girl with PKU and their nutritional formulations and design have improved over time. Since 2008, a bioactive macropeptide has been used as a base for protein substitutes in PKU, with potential benefits of improved bone and gut health, nitrogen retention, and blood phenylalanine control. In 2018, animal studies showed that physiomimic technology coating the amino acids with a polymer allows a slow release of amino acids with an improved physiological profile. History has shown that in PKU, the protein substitute's efficacy is determined by its nutritional profile, amino acid composition, dose, timing, distribution, and an adequate energy intake. Protein substitutes are often given little importance, yet their pharmacological actions and clinical benefit are pivotal when managing PKU.
Topics: Amino Acids; Animals; Caseins; Child, Preschool; Dietary Proteins; Female; History, 20th Century; History, 21st Century; Humans; Nutritional Requirements; Peptide Fragments; Phenylalanine; Phenylketonurias; Phenylpyruvic Acids; Protein Hydrolysates; United Kingdom
PubMed: 33540516
DOI: 10.3390/nu13020484 -
International Journal of Molecular... Dec 2023Inborn errors of metabolism (IEMs) comprise a diverse group of monogenic disorders caused by enzyme deficiencies that result either in a toxic accumulation of metabolic... (Meta-Analysis)
Meta-Analysis Review
Inborn errors of metabolism (IEMs) comprise a diverse group of monogenic disorders caused by enzyme deficiencies that result either in a toxic accumulation of metabolic intermediates or a shortage of essential end-products. Certain IEMs, like phenylketonuria (PKU), necessitate stringent dietary intervention that could lead to microbiome dysbiosis, thereby exacerbating the clinical phenotype. The objective of this systematic review was to examine the impact of PKU therapies on the intestinal microbiota. This research was conducted following the PRISMA Statement, with data from PubMed, Scopus, ScienceDirect, and Web of Science. A total of 18 articles meeting the inclusion criteria were published from 2011 to 2022. Significant reductions in several taxonomic groups in individuals with PKU when compared to the control group were detected in a quantitative analysis conducted across seven studies. The meta-analysis synthesis indicates a contrast in biodiversity between PKU subjects and the control population. Additionally, the meta-regression results, derived from the Bacillota/Bacteroidota ratio data, suggest a potential influence of diet in adult PKU populations ( = 0.004). It is worth noting that the limited number of studies calls for further research and analysis in this area. Our findings indicate the necessity of enhancing understanding of microbiota variability in reaction to treatments among PKU subjects to design tailored therapeutic and nutritional interventions to prevent complications resulting from microbiota disruption.
Topics: Adult; Humans; Phenylketonurias; Diet; Gastrointestinal Microbiome
PubMed: 38139256
DOI: 10.3390/ijms242417428 -
International Journal of Molecular... Jul 2020A delicate intracellular balance among protein synthesis, folding, and degradation is essential to maintaining protein homeostasis or proteostasis, and it is challenged... (Review)
Review
A delicate intracellular balance among protein synthesis, folding, and degradation is essential to maintaining protein homeostasis or proteostasis, and it is challenged by genetic and environmental factors. Molecular chaperones and the ubiquitin proteasome system (UPS) play a vital role in proteostasis for normal cellular function. As part of protein quality control, molecular chaperones recognize misfolded proteins and assist in their refolding. Proteins that are beyond repair or refolding undergo degradation, which is largely mediated by the UPS. The importance of protein quality control is becoming ever clearer, but it can also be a disease-causing mechanism. Diseases such as phenylketonuria (PKU) and hereditary tyrosinemia-I (HT1) are caused due to mutations in and gene, resulting in reduced protein stability, misfolding, accelerated degradation, and deficiency in functional proteins. Misfolded or partially unfolded proteins do not necessarily lose their functional activity completely. Thus, partially functional proteins can be rescued from degradation by molecular chaperones and deubiquitinating enzymes (DUBs). Deubiquitination is an important mechanism of the UPS that can reverse the degradation of a substrate protein by covalently removing its attached ubiquitin molecule. In this review, we discuss the importance of molecular chaperones and DUBs in reducing the severity of PKU and HT1 by stabilizing and rescuing mutant proteins.
Topics: Animals; Deubiquitinating Enzymes; Humans; Molecular Chaperones; Phenylketonurias; Proteasome Endopeptidase Complex; Protein Folding; Protein Stability; Proteolysis; Tyrosinemias; Ubiquitination
PubMed: 32679806
DOI: 10.3390/ijms21144996 -
Ugeskrift For Laeger Feb 2015Primary phenylalanine hydroxylase deficiency, also known as phenylketonuria, results in accumulation of phenylalanine in the blood. Early identification and treatment... (Review)
Review
Primary phenylalanine hydroxylase deficiency, also known as phenylketonuria, results in accumulation of phenylalanine in the blood. Early identification and treatment prevents the majority of clinical sequelae to the disease, but psychological and neurodevelopmental problems can occur in some patients. This article reviews the symptoms, diagnosis, classification and strategies of treatment and management of phenylketonuria. Finally we review new pharmacological and non-pharmaco-logical means of treatment.
Topics: Biopterins; Denmark; Diet, Protein-Restricted; Dietary Supplements; Humans; Phenylalanine; Phenylketonurias
PubMed: 25697170
DOI: No ID Found -
The Turkish Journal of Pediatrics 2022Phenylketonuria (PKU), is an autosomal recessive disease leading to the conversion defect of phenylalanine (Phe) into tyrosine. Severe neurocognitive and behavioral...
BACKGROUND
Phenylketonuria (PKU), is an autosomal recessive disease leading to the conversion defect of phenylalanine (Phe) into tyrosine. Severe neurocognitive and behavioral outcomes are observed in untreated cases. The present paper aims to review clinical experiences and expert recommendations in diagnosis, treatment, and follow-up of pediatric PKU patients in Turkey.
METHODS
Two advisory board meetings were held in the year 2016 and 2017 with contributions of four leading experts in this field, and an online update meeting was held for final decisions about statements, and conclusions in January 2021. Considering management gaps in diagnosis, treatment, and follow-up of PKU, discussion points are defined. The Committee members then reviewed the Turkish and general literature and the final statements were formulated.
RESULTS
The diagnostic cut-off for dried blood spots should remain at 2 mg/dl. Treatment cut-off value is acceptable at 6 mg/dl. Compliance with an ideal follow-up list is strongly recommended. Total protein intake should not be limited. Age-related safe levels of protein intake should be encouraged with an additional 40% from L-amino acids supplements, a 20% compensatory factor to account for the digestibility and utilization of amino acids from the supplement, and a further 20% compensation to optimize Phe control. Cognitive impairment and intelligence quotient evaluations should be performed at least twice before 3 years of age. In pregnant women, the target Phe level should be < 5 mg/dl, and they should be followed-up weekly in the first trimester, then every 2 weeks after organogenesis. Novel pharmacological treatments are promising, but some of them have limitations for our country.
CONCLUSIONS
Early diagnosis and treatment initiation; determination and standardization of diagnostic and treatment thresholds; treatment modalities and follow-up parameters are significant steps in treating PKU in the long term. PKU follow-up is a dynamic process with uncertainties and differences in clinical practice.
Topics: Amino Acids; Biopterins; Child; Female; Humans; Phenylalanine; Phenylketonurias; Pregnancy; Turkey
PubMed: 35899555
DOI: 10.24953/turkjped.2021.4098