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Denise M Ney - One of the best experts on this subject based on the ideXlab platform.
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dietary amino acid intakes associated with a low phenylalanine diet combined with amino acid medical foods and glycomacropeptide medical foods and neuropsychological outcomes in subjects with Phenylketonuria
Data in Brief, 2017Co-Authors: Bridget M Stroup, Sangita G Murali, Nivedita Nair, Emily A Sawin, Fran Rohr, Harvey L Levy, Denise M NeyAbstract:Abstract This article provides original data on median dietary intake of 18 amino acids from amino acid medical foods, glycomacropeptide medical foods, and natural foods based on 3-day food records obtained from subjects with Phenylketonuria who consumed low-phenylalanine diets in combination with amino acid medical foods and glycomacropeptide medical foods for 3 weeks each in a crossover design. The sample size of 30 subjects included 20 subjects with classical Phenylketonuria and 10 with a milder or variant form of Phenylketonuria. Results are presented for the Delis-Kaplan Executive Function System and the Cambridge Neuropsychological Test Automated Battery; the tests were administered at the end of each 3-week dietary treatment with amino acid medical foods and glycomacropeptide medical foods. The data are supplemental to our clinical trial, entitled “Glycomacropetide for nutritional management of Phenylketonuria: a randomized, controlled, crossover trial, 2016 (1) and “Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in Phenylketonuria, 2017 (2). This data has been made public and has utility to clinicians and researchers due to the following: 1) This provides the first comprehensive report of typical intakes of 18 amino acids from natural foods, as well as amino acid and glycomacropeptide medical foods in adolescents and adults with Phenylketonuria; and 2) This is the first evidence of similar standardized neuropsychological testing data in adolescents and adults with early-treated Phenylketonuria who consumed amino acid and glycomacropeptide medical foods.
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designing medical foods for inherited metabolic disorders why intact protein is superior to amino acids
Current Opinion in Biotechnology, 2017Co-Authors: Denise M Ney, Mark R EtzelAbstract:Phenylketonuria and tyrosinemia are inherited metabolic disorders characterized by high blood levels of phenylalanine (Phe) or tyrosine (Tyr), due to mutations in genes affecting Phe and Tyr metabolism, respectively. The primary management is a lifelong diet restricted in protein from natural foods in combination with medical foods comprised mixtures of synthetic amino acids. Compliance is often poor after childhood leading to neuropsychological sequela. Glycomacropeptide, an intact 64 amino acid glycophosphopeptide isolated from cheese whey, provides a new paradigm for the management of Phenylketonuria and tyrosinemia because glycomacropeptide contains no Phe and Tyr in its pure form, and is also a prebiotic. Medical foods made from glycomacropeptide have been used successfully for the management of Phenylketonuria and tyrosinemia. Preclinical and clinical studies demonstrate that intact protein from glycomacropeptide provides a more acceptable and physiologic source of defined protein compared to amino acids in medical foods. For example, harmful gut bacteria were reduced, beneficial short chain fatty acids increased, renal workload decreased, protein utilization increased, and bone fragility decreased using intact protein versus amino acids. Advances in biotechnology will propel the transition from synthetic amino acids to intact proteins for the management of inherited metabolic disorders.
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glycomacropeptide for nutritional management of Phenylketonuria a randomized controlled crossover trial
The American Journal of Clinical Nutrition, 2016Co-Authors: Denise M Ney, Sangita G Murali, Bridget M Stroup, Murray K Clayton, Gregory M Rice, Frances Rohr, Harvey L LevyAbstract:Background To prevent cognitive impairment, Phenylketonuria requires lifelong management of blood phenylalanine (Phe) concentration with a low-Phe diet. The diet restricts intake of Phe from natural proteins in combination with traditional amino acid medical foods (AA-MFs) or glycomacropeptide medical foods (GMP-MFs) that contain primarily intact protein and a small amount of Phe. Objective We investigated the efficacy and safety of a low-Phe diet combined with GMP-MFs or AA-MFs providing the same quantity of protein equivalents in free-living subjects with Phenylketonuria. Design This 2-stage, randomized crossover trial included 30 early-treated Phenylketonuria subjects (aged 15-49 y), 20 with classical and 10 with variant Phenylketonuria. Subjects consumed, in random order for 3 wk each, their usual low-Phe diet combined with AA-MFs or GMP-MFs. The treatments were separated by a 3-wk washout with AA-MFs. Fasting plasma amino acid profiles, blood Phe concentrations, food records, and neuropsychological tests were obtained. Results The frequency of medical food intake was higher with GMP-MFs than with AA-MFs. Subjects rated GMP-MFs as more acceptable than AA-MFs and noted improved gastrointestinal symptoms and less hunger with GMP-MFs. ANCOVA indicated no significant mean ± SE increase in plasma Phe (62 ± 40 μmol/L, P = 0.136), despite a significant increase in Phe intake from GMP-MFs (88 ± 6 mg Phe/d, P = 0.026). AA-MFs decreased plasma Phe (-85 ± 40 μmol/L, P = 0.044) with stable Phe intake. Blood concentrations of Phe across time were not significantly different (AA-MFs = 444 ± 34 μmol/L, GMP-MFs = 497 ± 34 μmol/L), suggesting similar Phe control. Results of the Behavior Rating Inventory of Executive Function were not significantly different. Conclusions GMP-MFs provide a safe and acceptable option for the nutritional management of Phenylketonuria. The greater acceptability and fewer side effects noted with GMP-MFs than with AA-MFs may enhance dietary adherence for individuals with Phenylketonuria. This trial was registered at www.clinicaltrials.gov as NCT01428258.
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glycomacropeptide is a prebiotic that reduces desulfovibrio bacteria increases cecal short chain fatty acids and is anti inflammatory in mice
American Journal of Physiology-gastrointestinal and Liver Physiology, 2015Co-Authors: Emily A Sawin, Sangita G Murali, Bridget M Stroup, Travis J De Wolfe, Busra Aktas, James L Steele, Denise M NeyAbstract:Glycomacropeptide (GMP) is a 64-amino acid (AA) glycophosphopeptide with application to the nutritional management of Phenylketonuria (PKU), obesity, and inflammatory bowel disease (IBD). GMP is a ...
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dietary protein source impacts bone acid load and calcium excretion in murine and human Phenylketonuria
The FASEB Journal, 2015Co-Authors: Bridget M Stroup, Sangita G Murali, Emily A Sawin, Denise M NeyAbstract:Background: Phenylketonuria (PKU) is caused by a loss of function mutations in phenylalanine (phe) hydroxylase and requires lifelong dietary management with an elemental amino acid (AA) or glycomac...
Aurora Martinez - One of the best experts on this subject based on the ideXlab platform.
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linking genotypes database with locus specific database and genotype phenotype correlation in Phenylketonuria
European Journal of Human Genetics, 2015Co-Authors: Sarah Wettstein, Aurora Martinez, Jarl Underhaug, Belen Perez, Brian D Marsden, W W Yue, Nenad BlauAbstract:The wide range of metabolic phenotypes in Phenylketonuria is due to a large number of variants causing variable impairment in phenylalanine hydroxylase function. A total of 834 phenylalanine hydroxylase gene variants from the locus-specific database PAHvdb and genotypes of 4181 Phenylketonuria patients from the BIOPKU database were characterized using FoldX, SIFT Blink, Polyphen-2 and SNPs3D algorithms. Obtained data was correlated with residual enzyme activity, patients' phenotype and tetrahydrobiopterin responsiveness. A descriptive analysis of both databases was compiled and an interactive viewer in PAHvdb database was implemented for structure visualization of missense variants. We found a quantitative relationship between phenylalanine hydroxylase protein stability and enzyme activity (r(s) = 0.479), between protein stability and allelic phenotype (r(s) = -0.458), as well as between enzyme activity and allelic phenotype (r(s) = 0.799). Enzyme stability algorithms (FoldX and SNPs3D), allelic phenotype and enzyme activity were most powerful to predict patients' phenotype and tetrahydrobiopterin response. Phenotype prediction was most accurate in deleterious genotypes (≈ 100%), followed by homozygous (92.9%), hemizygous (94.8%), and compound heterozygous genotypes (77.9%), while tetrahydrobiopterin response was correctly predicted in 71.0% of all cases. To our knowledge this is the largest study using algorithms for the prediction of patients' phenotype and tetrahydrobiopterin responsiveness in Phenylketonuria patients, using data from the locus-specific and genotypes database.
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l phenylalanine binding and domain organization in human phenylalanine hydroxylase a differential scanning calorimetry study
Biochemistry, 2002Co-Authors: Matthias Thorolfsson, Beatriz Ibarramolero, Peter Fojan, Steffen B Petersen, Jose M Sanchezruiz, Aurora MartinezAbstract:Human phenylalanine hydroxylase (hPAH) is a tetrameric enzyme that catalyzes the hydroxylation of l-phenylalanine (l-Phe) to l-tyrosine; a dysfunction of this enzyme causes Phenylketonuria. Each su...
Søren W Gersting - One of the best experts on this subject based on the ideXlab platform.
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Mapping the functional landscape of frequent phenylalanine hydroxylase ( PAH ) genotypes promotes personalised medicine in Phenylketonuria
Journal of Medical Genetics, 2015Co-Authors: Marta Danecka, Mathias Woidy, Johannes Zschocke, François Feillet, Ania C Muntau, Søren W GerstingAbstract:Background In Phenylketonuria, genetic heterogeneity, frequent compound heterozygosity, and the lack of functional data for phenylalanine hydroxylase genotypes hamper reliable phenotype prediction and individualised treatment. Methods A literature search revealed 690 different phenylalanine hydroxylase genotypes in 3066 Phenylketonuria patients from Europe and the Middle East. We determined phenylalanine hydroxylase function of 30 frequent homozygous and compound heterozygous genotypes covering 55% of the study population, generated activity landscapes, and assessed the phenylalanine hydroxylase working range in the metabolic (phenylalanine) and therapeutic (tetrahydrobiopterin) space. Results Shared patterns in genotype-specific functional landscapes were linked to biochemical and pharmacological phenotypes, where (1) residual activity below 3.5% was associated with classical Phenylketonuria unresponsive to pharmacological treatment; (2) lack of defined peak activity induced loss of response to tetrahydrobiopterin; (3) a higher cofactor need was linked to inconsistent clinical phenotypes and low rates of tetrahydrobiopterin response; and (4) residual activity above 5%, a defined peak of activity, and a normal cofactor need were associated with pharmacologically treatable mild phenotypes. In addition, we provide a web application for retrieving country-specific information on genotypes and genotype-specific phenylalanine hydroxylase function that warrants continuous extension, updates, and research on demand. Conclusions The combination of genotype-specific functional analyses with biochemical, clinical, and therapeutic data of individual patients may serve as a powerful tool to enable phenotype prediction and to establish personalised medicine strategies for dietary regimens and pharmacological treatment in Phenylketonuria.
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Phenylketonuria as a model for protein misfolding diseases and for the development of next generation orphan drugs for patients with inborn errors of metabolism
Journal of Inherited Metabolic Disease, 2010Co-Authors: Ania C Muntau, Søren W GerstingAbstract:The lecture dedicated to Professor Horst Bickel describes the advances, successes, and opportunities concerning the understanding of the biochemical and molecular basis of Phenylketonuria and the innovative treatment strategies introduced for these patients during the last 60 years. These concepts were transferred to other inborn errors of metabolism and led to significant reduction in morbidity and to an improvement in quality of life. Important milestones were the successful development of a low-phenylalanine diet for Phenylketonuria patients, the recognition of tetrahydrobiopterin as an option to treat these individuals pharmacologically, and finally market approval of this drug. The work related to the discovery of a pharmacological treatment led metabolic researchers and pediatricians to new insights into the molecular processes linked to mutations in the phenylalanine hydroxylase gene at the cellular and structural level. Again, Phenylketonuria became a prototype disorder for a previously underestimated but now rapidly expanding group of diseases: protein misfolding disorders with loss of function. Due to potential general biological mechanisms underlying these disorders, the door may soon open to a systematic development of a new class of pharmaceutical products. These pharmacological chaperones are likely to correct misfolding of proteins involved in numerous genetic and nongenetic diseases.
Charles R Scriver - One of the best experts on this subject based on the ideXlab platform.
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Phenylalanine hydroxylase deficiency
Genetics in Medicine, 2011Co-Authors: John J Mitchell, Yannis J Trakadis, Charles R ScriverAbstract:Phenylalanine hydroxylase deficiency is an autosomal recessive disorder that results in intolerance to the dietary intake of the essential amino acid phenylalanine. It occurs in approximately 1:15,000 individuals. Deficiency of this enzyme produces a spectrum of disorders including classic Phenylketonuria, mild Phenylketonuria, and mild hyperphenylalaninemia. Classic Phenylketonuria is caused by a complete or near-complete deficiency of phenylalanine hydroxylase activity and without dietary restriction of phenylalanine most children will develop profound and irreversible intellectual disability. Mild Phenylketonuria and mild hyperphenylalaninemia are associated with lower risk of impaired cognitive development in the absence of treatment. Phenylalanine hydroxylase deficiency can be diagnosed by newborn screening based on detection of the presence of hyperphenylalaninemia using the Guthrie microbial inhibition assay or other assays on a blood spot obtained from a heel prick. Since the introduction of newborn screening, the major neurologic consequences of hyperphenylalaninemia have been largely eradicated. Affected individuals can lead normal lives. However, recent data suggest that homeostasis is not fully restored with current therapy. Treated individuals have a higher incidence of neuropsychological problems. The mainstay of treatment for hyperphenylalaninemia involves a low-protein diet and use of a phenylalanine-free medical formula. This treatment must commence as soon as possible after birth and should continue for life. Regular monitoring of plasma phenylalanine and tyrosine concentrations is necessary. Targets of plasma phenylalanine of 120–360 μmol/L (2–6 mg/dL) in the first decade of life are essential for optimal outcome. Phenylalanine targets in adolescence and adulthood are less clear. A significant proportion of patients with Phenylketonuria may benefit from adjuvant therapy with 6R-tetrahydrobiopterin stereoisomer. Special consideration must be given to adult women with hyperphenylalaninemia because of the teratogenic effects of phenylalanine. Women with phenylalanine hydroxylase deficiency considering pregnancy should follow special guidelines and assure adequate energy intake with the proper proportion of protein, fat, and carbohydrates to minimize risks to the developing fetus. Molecular genetic testing of the phenylalanine hydroxylase gene is available for genetic counseling purposes to determine carrier status of at-risk relatives and for prenatal testing.
Ania C Muntau - One of the best experts on this subject based on the ideXlab platform.
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efficacy safety and population pharmacokinetics of sapropterin in pku patients 4 years results from the spark open label multicentre randomized phase iiib trial
Orphanet Journal of Rare Diseases, 2017Co-Authors: Ania C Muntau, Vincenzo Leuzzi, Alberto Burlina, Francois Eyskens, Peter Freisinger, Corinne De Laet, Frank Rutsch, Serap H Sivri, Suresh Vijay, Milva Orquidea BalAbstract:Sapropterin dihydrochloride, a synthetic formulation of BH4, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH4-responsive Phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of sapropterin dihydrochloride in children <4 years. In total, 109 male or female children <4 years with confirmed BH4-responsive Phenylketonuria or mild hyperphenylalaninemia and good adherence to dietary treatment were screened. 56 patients were randomly assigned (1:1) to 10 mg/kg/day oral sapropterin plus a phenylalanine-restricted diet or to only a phenylalanine-restricted diet for 26 weeks (27 to the sapropterin and diet group and 29 to the diet-only group; intention-to-treat population). Of these, 52 patients with ≥1 pharmacokinetic sample were included in the pharmacokinetic analysis, and 54 patients were included in the safety analysis. At week 26 in the sapropterin plus diet group, mean phenylalanine tolerance was 30.5 (95% confidence interval 18.7–42.3) mg/kg/day higher than in the diet-only group (p < 0.001). The safety profile of sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Using non-linear mixed effect modelling, a one-compartment model with flip-flop pharmacokinetic behaviour, in which the effect of weight was substantial, best described the pharmacokinetic profile. Patients in both groups had normal neuromotor development and stable growth parameters. The addition of sapropterin to a phenylalanine-restricted diet was well tolerated and led to a significant improvement in phenylalanine tolerance in children <4 years with BH4-responsive Phenylketonuria or mild hyperphenylalaninemia. The pharmacokinetic model favours once per day dosing with adjustment for weight. Based on the SPARK trial results, sapropterin has received EU approval to treat patients <4 years with BH4-responsive Phenylketonuria. ClinicalTrials.gov, NCT01376908 . Registered June 17, 2011.
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Mapping the functional landscape of frequent phenylalanine hydroxylase ( PAH ) genotypes promotes personalised medicine in Phenylketonuria
Journal of Medical Genetics, 2015Co-Authors: Marta Danecka, Mathias Woidy, Johannes Zschocke, François Feillet, Ania C Muntau, Søren W GerstingAbstract:Background In Phenylketonuria, genetic heterogeneity, frequent compound heterozygosity, and the lack of functional data for phenylalanine hydroxylase genotypes hamper reliable phenotype prediction and individualised treatment. Methods A literature search revealed 690 different phenylalanine hydroxylase genotypes in 3066 Phenylketonuria patients from Europe and the Middle East. We determined phenylalanine hydroxylase function of 30 frequent homozygous and compound heterozygous genotypes covering 55% of the study population, generated activity landscapes, and assessed the phenylalanine hydroxylase working range in the metabolic (phenylalanine) and therapeutic (tetrahydrobiopterin) space. Results Shared patterns in genotype-specific functional landscapes were linked to biochemical and pharmacological phenotypes, where (1) residual activity below 3.5% was associated with classical Phenylketonuria unresponsive to pharmacological treatment; (2) lack of defined peak activity induced loss of response to tetrahydrobiopterin; (3) a higher cofactor need was linked to inconsistent clinical phenotypes and low rates of tetrahydrobiopterin response; and (4) residual activity above 5%, a defined peak of activity, and a normal cofactor need were associated with pharmacologically treatable mild phenotypes. In addition, we provide a web application for retrieving country-specific information on genotypes and genotype-specific phenylalanine hydroxylase function that warrants continuous extension, updates, and research on demand. Conclusions The combination of genotype-specific functional analyses with biochemical, clinical, and therapeutic data of individual patients may serve as a powerful tool to enable phenotype prediction and to establish personalised medicine strategies for dietary regimens and pharmacological treatment in Phenylketonuria.
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Phenylketonuria as a model for protein misfolding diseases and for the development of next generation orphan drugs for patients with inborn errors of metabolism
Journal of Inherited Metabolic Disease, 2010Co-Authors: Ania C Muntau, Søren W GerstingAbstract:The lecture dedicated to Professor Horst Bickel describes the advances, successes, and opportunities concerning the understanding of the biochemical and molecular basis of Phenylketonuria and the innovative treatment strategies introduced for these patients during the last 60 years. These concepts were transferred to other inborn errors of metabolism and led to significant reduction in morbidity and to an improvement in quality of life. Important milestones were the successful development of a low-phenylalanine diet for Phenylketonuria patients, the recognition of tetrahydrobiopterin as an option to treat these individuals pharmacologically, and finally market approval of this drug. The work related to the discovery of a pharmacological treatment led metabolic researchers and pediatricians to new insights into the molecular processes linked to mutations in the phenylalanine hydroxylase gene at the cellular and structural level. Again, Phenylketonuria became a prototype disorder for a previously underestimated but now rapidly expanding group of diseases: protein misfolding disorders with loss of function. Due to potential general biological mechanisms underlying these disorders, the door may soon open to a systematic development of a new class of pharmaceutical products. These pharmacological chaperones are likely to correct misfolding of proteins involved in numerous genetic and nongenetic diseases.
