Pegvaliase: Immunological profile and recommendations for the clinical management of hypersensitivity reactions in patients with phenylketonuria treated with this enzyme substitution therapy
ConclusionsOverall, it was agreed that pegvaliase has a generally tolerable safety profile in adults with PKU. Importantly, the risk mitigation strategies utilized in the clinical trials were considered to support the continued use of key strategies for management in the commercial setting, such as a slow induction/titration dosing paradigm and premedication with H1-receptor antagonists. However, physicians and patients need to be aware of the risk of HAEs associated with pegvaliase; presence of a trained observer during early treatment may be beneficial in certain circumstances, and a requirement to carry auto-injectable ...
Source: Molecular Genetics and Metabolism - June 18, 2019 Category: Genetics & Stem Cells Source Type: research

Genes, Vol. 10, Pages 459: Structural and Functional Impact of Seven Missense Variants of Phenylalanine Hydroxylase
asi Andrea Soltysova The molecular genetics of well-characterized inherited diseases, such as phenylketonuria (PKU) and hyperphenylalaninemia (HPA) predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene, is often complicated by the identification of many novel variants, often with no obvious impact on the associated disorder. To date, more than 1100 PAH variants have been identified of which a substantial portion have unknown clinical significance. In this work, we study the functionality of seven yet uncharacterized PAH missense variants p.Asn167Tyr, p.Thr200Asn, p.Asp229Gly, p.Gly239Ala, p.Ph...
Source: Genes - June 15, 2019 Category: Genetics & Stem Cells Authors: Martina Pecimonova Daniela Kluckova Frantisek Csicsay Kamila Reblova Jan Krahulec Dagmar Proch ázkova Ludovit Skultety Ludevit Kadasi Andrea Soltysova Tags: Article Source Type: research

Replacement of breastfeeding with medical food for the treatment of galactosemia and phenylketonuria: maternal stress
Journal Name: Journal of Pediatric Endocrinology and Metabolism Issue: Ahead of print (Source: Journal of Pediatric Endocrinology and Metabolism)
Source: Journal of Pediatric Endocrinology and Metabolism - June 13, 2019 Category: Endocrinology Source Type: research

Protein Misfolding Diseases and Therapeutic Approaches.
Abstract Protein folding is the process by which a polypeptide chain acquires its functional, native 3D structure. Protein misfolding, on the other hand, is a process in which proteins fails to fold into its native functional conformation. This misfolding of proteins may lead to precipitation of number of serious diseases such as Cystic fibrosis (CF), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) etc. Protein quality-control (PQC) systems, consisting of molecular chaperones, proteases and regulatory factors, help in protein folding and prevent its aggregation. At the s...
Source: Current Protein and Peptide Science - June 9, 2019 Category: Biochemistry Authors: Yadav K, Yadav A, Priyanka, Pandey VP, Dwivedi UN Tags: Curr Protein Pept Sci Source Type: research

Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin [Biochemistry]
Phenylalanine hydroxylase (PAH) is a key enzyme in the catabolism of phenylalanine, and mutations in this enzyme cause phenylketonuria (PKU), a genetic disorder that leads to brain damage and mental retardation if untreated. Some patients benefit from supplementation with a synthetic formulation of the cofactor tetrahydrobiopterin (BH4) that partly acts... (Source: Proceedings of the National Academy of Sciences)
Source: Proceedings of the National Academy of Sciences - June 4, 2019 Category: Science Authors: Marte Innselset Flydal, Martin Alcorlo–Pages, Fredrik Gullaksen Johannessen, Siseth Martinez–Caballero, Lars Skȷarven, Rafael Fernandez–Leiro, Aurora Martinez, Juan A. Hermoso Tags: Biological Sciences Source Type: research

Clinical characterization of tremor in patients with phenylketonuria
Publication date: Available online 3 June 2019Source: Molecular Genetics and MetabolismAuthor(s): Francesca Nardecchia, Filippo Manti, Sabrina De Leo, Claudia Carducci, Vincenzo LeuzziAbstractBackgroundPhenylketonuria (PKU) is due to the deficit of the enzyme phenylalanine hydroxylase, the first step of dopamine synthesis. If not early treated the disease results in severe neurological impairment. Minor neurological signs have been reported in early treated PKU (ETPKU) subjects. Prolactin level is affected by (and reflects) brain dopamine availability. Object of the study was to assess the occurrence, age at onset, distrib...
Source: Molecular Genetics and Metabolism - June 3, 2019 Category: Genetics & Stem Cells Source Type: research

The European Phenylketonuria Guidelines and the challenges on management practices in Portugal
Journal Name: Journal of Pediatric Endocrinology and Metabolism Issue: Ahead of print (Source: Journal of Pediatric Endocrinology and Metabolism)
Source: Journal of Pediatric Endocrinology and Metabolism - May 29, 2019 Category: Endocrinology Source Type: research

The European Phenylketonuria Guidelines and the challenges on management practices in Portugal
Journal Name: Journal of Pediatric Endocrinology and Metabolism Volume: 32 Issue: 6 Pages: 623-629 (Source: Journal of Pediatric Endocrinology and Metabolism)
Source: Journal of Pediatric Endocrinology and Metabolism - May 29, 2019 Category: Endocrinology Source Type: research

[ASAP] Detection of Phenylketonuria Markers Using a ZIF-67 Encapsulated PtPd Alloy Nanoparticle (PtPd@ZIF-67)-Based Disposable Electrochemical Microsensor
ACS Applied Materials& InterfacesDOI: 10.1021/acsami.9b05431 (Source: ACS Applied Materials and Interfaces)
Source: ACS Applied Materials and Interfaces - May 28, 2019 Category: Materials Science Authors: Xinyue Xu †?, Dongqing Ji†?, Yuan Zhang*†, Xinghua Gao†, Pengcheng Xu‡, Xinxin Li‡, Chung-Chiun Liu§, and Weijia Wen† Source Type: research

A series of three case reports in patients with phenylketonuria performing regular exercise: first steps in dietary adjustment
Journal Name: Journal of Pediatric Endocrinology and Metabolism Issue: Ahead of print (Source: Journal of Pediatric Endocrinology and Metabolism)
Source: Journal of Pediatric Endocrinology and Metabolism - May 22, 2019 Category: Endocrinology Source Type: research

A series of three case reports in patients with phenylketonuria performing regular exercise: first steps in dietary adjustment
Journal Name: Journal of Pediatric Endocrinology and Metabolism Volume: 32 Issue: 6 Pages: 635-641 (Source: Journal of Pediatric Endocrinology and Metabolism)
Source: Journal of Pediatric Endocrinology and Metabolism - May 21, 2019 Category: Endocrinology Source Type: research

In vitro residual activities in 20 variants of phenylalanine hydroxylase and genotype-phenotype correlation in phenylketonuria patients.
In this study, the spectrum of PAH variants in 1083 Chinese PKU patients was analyzed. Then 20 variants (p.L52F, p.R86P, p.L128P, p.L142P, p.D163N, p.C203G, p.E214G, p.F260L, p.M276T, p.L311R, p.P314A, p.L364F, p.Q375H, p.F382I, p.A395S, p.V412D, p.E108*, p.C203*, p.C284* and p.E353*) were expressed in COS-7 cells. The residual activities and protein expression levels were detected by isotope-dilution liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) and Western blotting, respectively. We compared the results of the phenotypic prediction based on APV and PAH activity respectively, and fu...
Source: Gene - May 15, 2019 Category: Genetics & Stem Cells Authors: Zhang X, Ye J, Shen N, Tao Y, Han L, Qiu W, Zhang H, Liang L, Fan Y, Wang J, Gong Z, Wang Y, You G, Fu Q, Mo X, Gu X, Yu Y Tags: Gene Source Type: research

Comparison of liquid chromatography with tandem mass spectrometry and ion-exchange chromatography by post-column ninhydrin derivatization for amino acid monitoring
Publication date: Available online 8 May 2019Source: Clinica Chimica ActaAuthor(s): Andraz Smon, Vanja Cuk, Jernej Brecelj, Simona Murko, Urh Groselj, Mojca Zerjav Tansek, Tadej Battelino, Barbka Repic LampretAbstractObjectivesPrecise quantification of amino acids (AAs) is mandatory for successful diagnosis and monitoring of patients with metabolic diseases. We compared ion-exchange chromatography (IEC) and liquid chromatography with tandem mass spectrometry (LC-MS/MS), the two methods most commonly used in clinical laboratories for the quantification of AAs in physiological samples.Design & methods123 apparently healt...
Source: Clinica Chimica Acta - May 9, 2019 Category: Laboratory Medicine Source Type: research

Comparison of liquid chromatography with tandem mass spectrometry and ion-exchange chromatography by post-column ninhydrin derivatization for amino acid monitoring.
Abstract OBJECTIVES: Precise quantification of amino acids (AAs) is mandatory for successful diagnosis and monitoring of patients with metabolic diseases. We compared ion-exchange chromatography (IEC) and liquid chromatography with tandem mass spectrometry (LC-MS/MS), the two methods most commonly used in clinical laboratories for the quantification of AAs in physiological samples. DESIGN & METHODS: 123 apparently healthy children were selected for the study. The plasma samples for LC-MS/MS were prepared accordingly to the aTRAQ Kit for Physiological Fluids on Sciex 3200 Qtrap, for IEC according to the pr...
Source: International Journal of Clinical Chemistry - May 8, 2019 Category: Chemistry Authors: Smon A, Cuk V, Brecelj J, Murko S, Groselj U, Tansek MZ, Battelino T, Lampret BR Tags: Clin Chim Acta Source Type: research

Maternal phenylketonuria in Turkey: outcomes of 71 pregnancies and issues in management
AbstractUntreated phenylketonuria (PKU) in pregnancy causes a severe embryopathy called maternal PKU syndrome. Here, we aimed to assess management issues and pregnancy outcomes in the first published series of PKU pregnancies from the developing world. Data were collected retrospectively in a single center from 71 pregnancies and 45 live births of 32 women with PKU, 11 of whom were diagnosed in adulthood after having an affected child. Microcephaly, intellectual disability, and dysmorphic facies were more prevalent in offspring of untreated than treated pregnancies with classical PKU (100% vs. 0%, 91% vs. 0%, and 73% vs. 23% withp 
Source: European Journal of Pediatrics - May 3, 2019 Category: Pediatrics Source Type: research

International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria
Publication date: Available online 26 April 2019Source: Molecular Genetics and MetabolismAuthor(s): Ania C. Muntau, Darius J. Adams, Amaya Bélanger-Quintana, Tatiana V. Bushueva, Roberto Cerone, Yin-Hsiu Chien, Ana Chiesa, Turgay Coşkun, Javier de las Heras, François Feillet, Rachel Katz, Florian Lagler, Flavia Piazzon, Fran Rohr, Francjan J. van Spronsen, Paula Vargas, Gisela Wilcox, Kaustuv BhattacharyaAbstractPhenylketonuria (PKU) is an inherited metabolic disease caused by phenylalanine hydroxylase (PAH) deficiency. As the resulting high blood phenylalanine (Phe) concentration can have detrimental effect...
Source: Molecular Genetics and Metabolism - April 28, 2019 Category: Genetics & Stem Cells Source Type: research

UK patients who tested Kuvan for phenylketonuria will get supplies after trials end, says company
(Source: BMJ News)
Source: BMJ News - April 24, 2019 Category: General Medicine Source Type: research

Self-Reported Anxiety, Depression and Coping in Parents of Children with Phenylketonuria
AbstractLimited published research has evaluated mental health in parents of children with phenylketonuria (PKU) and their coping strategies. We aimed to assess anxiety, depression and coping in parents of Tunisian children treated for PKU. We conducted a cross-sectional study in the reference center for the management of inherited metabolic diseases in Tunisia. We used the Hospital Anxiety and Depression (HAD) scale and the Brief-COPE. Dependent variables were anxiety, depression, HAD Depression (HADD) and Anxiety (HADA) scores, and coping scores. Linear regression and logistic binary regression were used for multivariate...
Source: Journal of Developmental and Physical Disabilities - April 24, 2019 Category: Disability Source Type: research

Phenylketonuria Diet Promotes Shifts in Firmicutes Populations
In this study we compared the gut microbial communities of children with PKU and with mild hyperphenylalaninemia (MHP, unrestricted diet). For each group, we enrolled 21 children (4–18 years old), for a total dataset of 42 subjects. We assessed dietary intake and performed gut microbiota analysis by sequencing the V3–V4 hypervariable regions of the 16S rRNA gene. Short chain fatty acids (SCFAs) were quantified by gas chromatographic analysis. While alpha-diversity analysis showed no significant differences between PKU and MHP groups, microbial community analysis highlighted a significant separation of the gut m...
Source: Frontiers in cellular and infection microbiology - April 16, 2019 Category: Microbiology Source Type: research

Can the Microbiome Deliver? A Proof-of-Concept Engineered E.  coli PKU Therapeutic.
Can the Microbiome Deliver? A Proof-of-Concept Engineered E. coli PKU Therapeutic. Cell Host Microbe. 2019 Apr 10;25(4):473-474 Authors: Alteri CJ Abstract Phenylketonuria (PKU) is a rare genetic disorder that causes phenylalanine toxicity in the brain. Two studies, Crook et al. (2019), in this issue of Cell Host & Microbe, and Isabella et al. (2018), employ synthetic biology to develop a live bacterial therapeutic to treat PKU and potentially other metabolic diseases. PMID: 30974078 [PubMed - in process] (Source: Cell Host and Microbe)
Source: Cell Host and Microbe - April 10, 2019 Category: Microbiology Authors: Alteri CJ Tags: Cell Host Microbe Source Type: research

Propagation of Plasma L-Phenylalanine Concentration Fluctuations to the Neurovascular Unit in Phenylketonuria: An in silico Study
Mehdi Taslimifar, Stefano Buoso, Francois Verrey, Vartan Kurtcuoglu (Source: Frontiers in Physiology)
Source: Frontiers in Physiology - April 2, 2019 Category: Physiology Source Type: research

Asymmetric dimethylarginine as a potential biomarker for management and follow-up of phenylketonuria
AbstractPhenylketonuria ’s (PKU) treatment based on low-protein diet may affect other metabolic pathways, such as that of asymmetric dimethylarginine (ADMA). The aim of this study was to evaluate the reliability of ADMA as a biomarker of adequate metabolic control and possible nutritional risk in a long-term PKU patient population. One hundred and six dietary-treated PKU patients from four hospitals in Spain were enrolled in this cross-sectional study. Their lipid profile, total homocysteine, ADMA, and symmetric dimethylarginine (SDMA) concentrations were analyzed and compared with a control group. Sensitivity, spe c...
Source: European Journal of Pediatrics - April 2, 2019 Category: Pediatrics Source Type: research

Case Report: Neuropsychiatric Symptoms in PKU Disease
Phenylketonuria is a rare inborn error of metabolism. The build-up of phenylalanine in the blood and body tissues can have significant impact on the brain's development. High phenylalanine levels have been shown to be associated with an increase in neuropsychiatric symptoms, including mood, anxiety, and attention problems; decreased social competence; and low self-esteem. This case report highlights such a presentation in an adolescent with phenylketonuria. (Source: Journal of Pediatric Health Care)
Source: Journal of Pediatric Health Care - March 29, 2019 Category: Pediatrics Authors: Kimberly J. Erlich Tags: Case Report Source Type: research

Diversity of phenylalanine tolerance in pregnant phenylketonuria patients homozygous for the p.R408W mutation: the need for improved understanding of phenylalanine homeostasis.
Authors: Hozyasz KK, Żółkowska J Abstract Dietetic treatment of phenylketonuria (PKU) includes a low-phenylalanine (phe) diet that provides sufficient phe for maintenance and growth plus special phe-free formulas with amino acids to meet requirements for protein, energy and micronutrients. PMID: 30907078 [PubMed - as supplied by publisher] (Source: Journal of Biological Regulators and Homeostatic Agents)
Source: Journal of Biological Regulators and Homeostatic Agents - March 26, 2019 Category: Biomedical Science Tags: J Biol Regul Homeost Agents Source Type: research

The evaluation of phenylalanine levels in Estonian phenylketonuria patients during eight years by electronic laboratory records
Publication date: June 2019Source: Molecular Genetics and Metabolism Reports, Volume 19Author(s): Hardo Lilleväli, Karit Reinson, Kai Muru, Siret Saarsalu, Kadi Künnapas, Tiina Kahre, Ülle Murumets, Katrin ÕunapAbstractBlood phenylalanine (Phe) values from the dried blood spots of all Estonian phenylketonuria (PKU) patients have been deposited into a unified electronic laboratory database for eight years, providing an opportunity to assess the adherence of the patients to dietary recommendations over time and to observe patient practices both individually and collectively. Our results demonstrate gene...
Source: Molecular Genetics and Metabolism Reports - March 24, 2019 Category: Genetics & Stem Cells Source Type: research

The phenylketonuria-associated substitution R68S converts phenylalanine hydroxylase to a constitutively active enzyme but reduces its stability [Molecular Bases of Disease]
The naturally occurring R68S substitution of phenylalanine hydroxylase (PheH) causes phenylketonuria (PKU). However, the molecular basis for how the R68S variant leads to PKU remains unclear. Kinetic characterization of R68S PheH establishes that the enzyme is fully active in the absence of allosteric binding of phenylalanine, in contrast to the WT enzyme. Analytical ultracentrifugation establishes that the isolated regulatory domain of R68S PheH is predominantly monomeric in the absence of phenylalanine and dimerizes in its presence, similar to the regulatory domain of the WT enzyme. Fluorescence and small-angle X-ray sca...
Source: Journal of Biological Chemistry - March 22, 2019 Category: Chemistry Authors: Crystal A. Khan, Steve P. Meisburger, Nozomi Ando, Paul F. Fitzpatrick Tags: Enzymology Source Type: research

Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals
In this study, we examined to what extent we can predict population frequencies of recessive disorders from genomic data, and explored better strategies for variant interpretation and classification. We used a whole-genome reference panel from 3552 general Japanese individuals constructed by the Tohoku Medical Megabank Organization (ToMMo). Focusing on 32 genes for 17 congenital metabolic disorders included in newborn screening (NBS) in Japan, we identified reported and predicted pathogenic variants through variant annotation, interpretation, and multiple ways of classifications. The estimated carrier frequencies were comp...
Source: Human Genetics - March 18, 2019 Category: Genetics & Stem Cells Source Type: research

Depletion of interfering IgG and IgM is critical to determine the role of IgE in pegvaliase-associated hypersensitivity.
Abstract Pegvaliase is an enzyme substitution therapy developed to lower blood phenylalanine (Phe) in adults with phenylketonuria (PKU). In phase 3 clinical studies, pegvaliase substantially reduced mean blood Phe in adult subjects with PKU. The most common type of adverse event observed in the pegvaliase clinical program was hypersensitivity adverse events (HAEs), which included occurrences of arthralgia, rash, and pruritis. The most clinically relevant HAEs were acute systemic hypersensitivity reactions consistent with anaphylaxis observed in 4.6% of phase 3 patients. HAEs were more commonly observed around the ...
Source: Journal of Immunological Methods - March 14, 2019 Category: Allergy & Immunology Authors: Larimore K, Nguyen T, Badillo B, Lau K, Zori R, Shepherd G, Zoog SJ, Weng HH, Gupta S Tags: J Immunol Methods Source Type: research

Phenylketonuria: Current Treatments and Future Developments
This article reviews the mainstay therapy, adjunct enzyme cofactor therapy, and the newly available enzyme substitution therapy for hyperphenylalaninemia. It also provides an outlook on emerging approaches for hyperphenylalaninemia treatment such as recruiting the microbiome into the therapeutic endeavor as well as therapies under development such as gene therapy. (Source: Drugs)
Source: Drugs - March 12, 2019 Category: Drugs & Pharmacology Source Type: research

Genotype ‐phenotype correlations and BH4 estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil
ConclusionThe high discordance rate between genotype ‐predicted and observed metabolic phenotypes in this study seems to be due partially to the high frequency of the so‐called “moderate” common mutations, p.R261Q, p.V388M, and p.I65T, which are reported to be associated to erratic or more severe than expected metabolic phenotypes. Although ou r results of BH4 estimated responsiveness must be regarded as tentative, it should be emphasized that genotyping and genotype ‐phenotype association studies are important in selecting patients to be offered a BH4 overload test, especially in low ‐resource settings...
Source: Molecular Genetics & Genomic Medicine - March 3, 2019 Category: Genetics & Stem Cells Authors: Eduardo Vieira Neto, Francisco Laranjeira, Dulce Quelhas, Isaura Ribeiro, Alexandre Seabra, Nicole Mineiro, Lilian M. Carvalho, L úcia Lacerda, Márcia G. Ribeiro Tags: ORIGINAL ARTICLE Source Type: research

The Effects of Ligand Deprotonation on the Binding Selectivity of the Phenylalanine Hydroxylase Active Site
We report promising novel catechols that do not inhibit this enzyme. Results show deprotonation of the ligands by the active site can strongly affecting their binding strength, thus the pKas for all novel ligands were calculated and are reported.Graphical abstractNew family of molecules (PG-X) that do not inhibit Phenylalanine Hydroxylase, thus making them possible drug candidates for raising levels of dopamine in the brain. Shown above is PG-OH, which has the weakest interaction energy when optimized in the Phenylalanine Hydroxylase active site. Optimization is performed with M062X/6-31G, implicit solvation, and relaxed a...
Source: Computational and Theoretical Chemistry - February 25, 2019 Category: Chemistry Source Type: research

Admissions and Cost of Hospitalisation of Phenylketonuria: Spanish Claims Database Analysis
ConclusionsThe access to economic and social data on phenylketonuria in Spain has been updated. The number of admissions in Spain between 1997 and 2015 and healthcare costs between 1999 and 2015 were calculated. There were 24 admissions as a result of a phenylketonuria diagnosis in 2015 and the mean healthcare cost per patient was €4239.32. This information can help to adapt and improve each healthcare system to take into consideration rare diseases. (Source: Clinical Drug Investigation)
Source: Clinical Drug Investigation - February 18, 2019 Category: Drugs & Pharmacology Source Type: research

Phenylketonuria
remains one of the most common inborn errors of metabolism. In the UK it is detected on the newborn heel-prick screening sample allowing early treatment with a strict low phenylalanine diet supplemented with artificial amino acids and appropriate vitamin and minerals. Although the long-term prognosis is good, there is an increasing body of evidence highlighting subtle problems in neuropsychological function with slower reaction times and poorer executive function than peers. White matter changes clearly seen on brain magnetic resonance imaging may have some relationship to these neuropsychological difficulties but their s...
Source: Paediatrics and Child Health - February 18, 2019 Category: Pediatrics Authors: Maureen Anne Cleary, Rachel Skeath Tags: Symposium: inborn errors of metabolism Source Type: research

Glycomacropeptide: long-term use and impact on blood phenylalanine, growth and nutritional status in children with PKU
In phenylketonuria, casein glycomacropeptide (CGMP) requires modification with the addition of some essential and semi essential amino acids to ensure suitability as a protein substitute. The optimal amount an... (Source: Orphanet Journal of Rare Diseases)
Source: Orphanet Journal of Rare Diseases - February 15, 2019 Category: Internal Medicine Authors: A. Daly, S. Evans, S. Chahal, S. Santra, A. Pinto, R. Jackson, C. Gingell, J. Rocha, F. J. Van Spronsen and A. MacDonald Tags: Research Source Type: research

Mutation spectrum of PAH gene in phenylketonuria patients in Northwest China: identification of twenty novel variants
In conclusion, the mutational spectrum underlying PKU in Northwest China was established for the first time. Functional analysis of 20 novelPAH gene variants enriched thePAH gene mutational spectrum. Correlation analysis between variants frequencies in compound heterozygous patients and phenotype severity is helpful for phenotypic prediction. (Source: Metabolic Brain Disease)
Source: Metabolic Brain Disease - February 12, 2019 Category: Neurology Source Type: research

Phase I clinical evaluation of CNSA-001 (sepiapterin), a novel pharmacological treatment for phenylketonuria and tetrahydrobiopterin deficiencies, in healthy volunteers
We report the results of a first-in-humans, randomized, double-blind, placebo-controlled, dose-ranging, Phase I clinical trial in 83 healthy volunteers of CNSA-001, a novel formulation of sepiapterin. Single oral doses of 2.5–80 mg/kg CNSA-001 caused dose-related increases in plasma sepiapterin (mean Cmax 0.58–2.92 ng/mL) and BH4 (mean Cmax 57–312 ng/mL). Maximum plasma concentrations were achieved in about 1–2 h (sepiapterin) or about 4 h (BH4) after CNSA-001 oral intake.Increases in plasma BH4 were substantially larger in absolute terms and on a dose-for-dose basis following treatment wi...
Source: Molecular Genetics and Metabolism - February 11, 2019 Category: Genetics & Stem Cells Source Type: research

Age-Specific Cut-off Values of Amino Acids and Acylcarnitines for Diagnosis of Inborn Errors of Metabolism Using Liquid Chromatography Tandem Mass Spectrometry.
In conclusion, along with establishment of a validated LC-MS/MS method for quantitation of AAs and ACs from the DBS cards, the study also demonstrates the presence of predominantly available IEMs in Bangladesh. PMID: 30723736 [PubMed - in process] (Source: Biomed Res)
Source: Biomed Res - February 8, 2019 Category: Research Authors: Sarker SK, Islam MT, Biswas A, Bhuyan GS, Sultana R, Sultana N, Rakhshanda S, Begum MN, Rahat A, Yeasmin S, Khanam M, Saha AK, Noor FA, Sajib AA, Islam ABMMK, Qadri SK, Shahidullah M, Mannan MA, Muraduzzaman AKM, Shirin T, Rahman SM, Qadri SS, Saha N, Akh Tags: Biomed Res Int Source Type: research

Screening and development of enzymes for determination and transformation of amino acids.
Abstract The high stereo- and substrate specificities of enzymes have been utilized for micro-determination of amino acids. Here, I review the discovery of l-Phe dehydrogenase and its practical use in the diagnosis of phenylketonuria in more than 5,400,000 neonates over two decades in Japan. Screening and uses of other selective enzymes for micro-determination of amino acids have also been discussed. In addition, novel enzymatic assays with the systematic use of known enzymes, including assays based on a pyrophosphate detection system using pyrophosphate dikinase for a variety of l-amino acids with amino-acyl-tRNA...
Source: Bioscience, Biotechnology, and Biochemistry - January 8, 2019 Category: Biochemistry Authors: Asano Y Tags: Biosci Biotechnol Biochem Source Type: research

Severe acute pancreatitis in a child with phenylketonuria.
We report for the first time severe acute pancreatitis in a child treated for phenylketonuria (PKU) discovered on neonatal screening. This 2-year-old boy was first hospitalized for bilious vomiting and moderate back pain. Laboratory values included a lipase level of 1.142 U/L, a phenylalanine level of 10mg/dL, and computed tomography revealed Balthazar grade E pancreatitis. Continuous enteral feeding was started on the 3rd day after admission. We observed clinical and biological improvement. Etiologic investigations for pancreatitis returned negative. Despite the severity of the pancreatitis, we did not observe decompensat...
Source: Archives de Pediatrie - January 6, 2019 Category: Pediatrics Authors: Bertrand V, Smokvina E, Masson E, Bruel H Tags: Arch Pediatr Source Type: research

Development of national consensus statements on food labelling interpretation and protein allocation in a low phenylalanine diet for PKU
In the treatment of phenylketonuria (PKU), there was disparity between UK dietitians regarding interpretation of how different foods should be allocated in a low phenylalanine diet (allowed without measurement... (Source: Orphanet Journal of Rare Diseases)
Source: Orphanet Journal of Rare Diseases - January 3, 2019 Category: Internal Medicine Authors: Sharon Evans, Suzanne Ford, Sarah Adam, Sandra Adams, Jane Ash, Catherine Ashmore, Gillian Caine, Rachel Carruthers, Sarah Cawtherley, Satnam Chahal, Anne Clark, Barbara Cochrane, Anne Daly, Karen Dines, Marjorie Dixon, Carolyn Dunlop & hellip; Tags: Research Source Type: research

Neurocognitive functioning in adults with phenylketonuria: Report of a 10-year follow-up
Publication date: Available online 26 December 2018Source: Molecular Genetics and MetabolismAuthor(s): R. Feldmann, J. Osterloh, S. Onon, J. Fromm, F. Rutsch, J. WeglageAbstractBackgroundThe long-term prognosis of early treated phenylketonuria (PKU) is still under discussion. Aim of this controlled long-term study was to assess the neurological and neuropsychological outcome in adult patients with early-treated PKU.MethodsWe investigated 35 patients with early-treated classical PKU aged 29 to 51 years (mean age 41 years) and 18 healthy controls matched for age and socioeconomic status. Patients and controls were assess...
Source: Molecular Genetics and Metabolism - December 27, 2018 Category: Genetics & Stem Cells Source Type: research

Simulations of the regulatory ACT domain of human phenylalanine hydroxylase (PAH) unveil its mechanism of phenylalanine binding [Enzymology]
Phenylalanine hydroxylase (PAH) regulates phenylalanine (Phe) levels in mammals to prevent neurotoxicity resulting from high Phe concentrations as observed in genetic disorders leading to hyperphenylalaninemia and phenylketonuria. PAH senses elevated Phe concentrations by transient allosteric Phe binding to a protein–protein interface between ACT domains of different subunits in a PAH tetramer. This interface is present in an activated PAH (A-PAH) tetramer and absent in a resting-state PAH (RS-PAH) tetramer. To investigate this allosteric sensing mechanism, here we used the GROMACS molecular dynamics simulation suite...
Source: Journal of Biological Chemistry - December 21, 2018 Category: Chemistry Authors: Yunhui Ge, Elias Borne, Shannon Stewart, Michael R. Hansen, Emilia C. Arturo, Eileen K. Jaffe, Vincent A. Voelz Tags: Editors ' Picks Source Type: research

Conformational selection turns on phenylalanine hydroxylase [Molecular Biophysics]
Phenylalanine hydroxylase catalyzes a critical step in the phenylalanine catabolic pathway, and impairment of the human enzyme is linked to phenylketonuria. Phenylalanine is also a positive allosteric regulator of the enzyme, and the allosteric binding site has been determined by crystallography. However, the allosteric activation mechanism remains unclear. Using large-scale simulations to explore how phenylalanine binds to the regulatory site, Ge et al. discovered gating motions of the protein that suggest a conformational selection mechanism. (Source: Journal of Biological Chemistry)
Source: Journal of Biological Chemistry - December 21, 2018 Category: Chemistry Authors: Kirill A. Konovalov, Wei Wang, Xuhui Huang Tags: Editors ' Picks Highlights Source Type: research

Parental awareness of newborn bloodspot screening in Ireland
AbstractBackgroundThere is little known regarding how familiar parents are with the newborn bloodspot screening (NBS) test or how well parents of a child with a screen-detected condition understand that condition initially.AimThe study aim was to examine parental NBS awareness and conditions screened.MethodsTwo studies were conducted: [1] Parents of children with cystic fibrosis (CF) detected via NBS and subsequently, diagnosed (n = 124) completed a telephone questionnaire regarding information they received at the time of NBS. [2] A cross-sectional study of women (n = 662 (58%) antenatal;n&thin...
Source: Irish Journal of Medical Science - December 15, 2018 Category: General Medicine Source Type: research

Evidence- and consensus-based recommendations for the use of pegvaliase in adults with phenylketonuria
Evidence- and consensus-based recommendations for the use of pegvaliase in adults with phenylketonuria, Published online: 14 December 2018; doi:10.1038/s41436-018-0403-zEvidence- and consensus-based recommendations for the use of pegvaliase in adults with phenylketonuria (Source: Genetics in Medicine)
Source: Genetics in Medicine - December 14, 2018 Category: Genetics & Stem Cells Authors: Nicola Longo David Dimmock Harvey Levy Krista Viau Heather Bausell Deborah A. Bilder Barbara Burton Christel Gross Hope Northrup Fran Rohr Stephanie Sacharow Amarilis Sanchez-Valle Mary Stuy Janet Thomas Jerry Vockley Roberto Zori Cary O. Harding Source Type: research

Identification and characterization of a sterically robust phenylalanine ammonia-lyase among 481 natural isoforms through association of in silico and in vitro studies
In conclusion, finding models with the most reasonable stereo-chemical quality and lowest numbers of steric clashes would result in easier folding. Hence, in silico analyses of bulk data from natural origin will lead one to find an optimal model for in vitro studies and drug design.Graphical abstract (Source: Enzyme and Microbial Technology)
Source: Enzyme and Microbial Technology - December 13, 2018 Category: Biotechnology Source Type: research

Weaning practices in phenylketonuria vary between health professionals in Europe
Publication date: Available online 25 November 2018Source: Molecular Genetics and Metabolism ReportsAuthor(s): A. Pinto, S. Adams, K. Ahring, H. Allen, M.F. Almeida, D. Garcia-Arenas, N. Arslan, M. Assoun, Y. Atik Altınok, D. Barrio-Carreras, A. Belanger Quintana, S.M. Bernabei, C. Bontemps, F. Boyle, G. Bruni, M. Bueno-Delgado, G. Caine, R. Carvalho, A. Chrobot, K. ChyżAbstractBackgroundIn phenylketonuria (PKU), weaning is considered more challenging when compared to feeding healthy infants. The primary aim of weaning is to gradually replace natural protein from breast milk or standard infant formula with solids contain...
Source: Molecular Genetics and Metabolism Reports - November 25, 2018 Category: Genetics & Stem Cells Source Type: research

Reproductive experience of women living with phenylketonuria
ConclusionsMany women with PKU have unmet sexual and reproductive health needs. Pregnancy fears are prominent from adolescence onwards and for some women overarching concerns about their ability to cope with pregnancy led to a decision not to have children. Interventions are needed to reduce the psychological impact of the risk of maternal PKU syndrome and assist with safe pregnancies. Post-natal experiences of women with PKU give rise to concern. (Source: Molecular Genetics and Metabolism Reports)
Source: Molecular Genetics and Metabolism Reports - November 4, 2018 Category: Genetics & Stem Cells Source Type: research

Behavioral and Emotional Problems in Early-Treated Brazilian Children and Adolescents with Phenylketonuria.
CONCLUSIONS Our findings indicate a significant prevalence of parents' complaints of attention problems and hyperactivity in non-adherent to treatment and intellectually low performing patients with PKU. PMID: 30375370 [PubMed - in process] (Source: Medical Science Monitor)
Source: Medical Science Monitor - November 1, 2018 Category: Research Tags: Med Sci Monit Source Type: research

One-year follow-up of B vitamin and Iron status in patients with phenylketonuria provided tetrahydrobiopterin (BH4)
People with Phenylketonuria (PKU) who respond to tetrahydrobiopterin (BH4) often decrease dependence on medical food (MF) following increased phenylalanine (phe) tolerance. Responders to BH4 may experience a r... (Source: Orphanet Journal of Rare Diseases)
Source: Orphanet Journal of Rare Diseases - October 30, 2018 Category: Internal Medicine Authors: Kristen D Brantley, Teresa D Douglas and Rani H Singh Tags: Research Source Type: research