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Yuchao Xia, Yun Liu, Minghua Deng, Ruibin Xi
Motivation: Structural variation (SV) is an important class of genomic variations in human genomes. A number of SV detection algorithms based on high-throughput sequencing data have been developed, but they have various and often limited level of sensitivity, specificity and breakpoint resolution. Furthermore, since overlaps between predictions of algorithms are low, SV detection based on multiple algorithms, an often-used strategy in real applications, has little effect in improving the performance of SV detection...
July 14, 2017: Bioinformatics
Rihwa Choi, Jeongho Lee, Hyung-Doo Park, Jong Eun Park, Yong Hyuk Kim, Chang-Seok Ki, Soo-Youn Lee, Junghan Song, Jong-Won Kim, Dong Hwan Lee
BACKGROUND: The accurate interpretation of sequence variation is critical for successful molecular diagnoses. It is also fundamental to the accurate diagnosis and treatment of phenylketonuria (PKU). This study aims to evaluate the significance of the c.158G>A (p.Arg53His) variant in the PAH gene, which was previously reported to be a pathogenic mutation that results in decreased phenylalanine hydroxylase enzyme activity in hyperphenylalaninemia (HPA) patients. METHODS: Seven unrelated Korean patients with HPA genotyped with the c...
October 16, 2017: Journal of Pediatric Endocrinology & Metabolism: JPEM
S Doyle, M O'Regan, C Stenson, J Bracken, U Hendroff, A Agasarova, D Deverell, E P Treacy
Adherence to dietary and treatment recommendations is a long-standing concern for adults and adolescents with PKU and treating clinicians. In about 20-30% of PKU patients, Phe levels may be controlled by tetrahydrobiopterin (BH4) therapy. The European PKU 2017 Guidelines recommends treatment with BH4 for cases of proven long-term BH4 responsiveness, with a recommended dosage of Sapropterin 10-20 mg/kg/day.We report four young Irish patients with mild PKU, known to be BH4 responsive, who were treated with lower doses of Sapropterin for over 7 years...
October 14, 2017: JIMD Reports
A M J van Wegberg, A MacDonald, K Ahring, A Bélanger-Quintana, N Blau, A M Bosch, A Burlina, J Campistol, F Feillet, M Giżewska, S C Huijbregts, S Kearney, V Leuzzi, F Maillot, A C Muntau, M van Rijn, F Trefz, J H Walter, F J van Spronsen
Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method...
October 12, 2017: Orphanet Journal of Rare Diseases
Alicia de la Parra, María Ignacia García, Valerie Hamilton, Carolina Arias, Juan Francisco Cabello, Verónica Cornejo
There is a consensus on the importance of early and life-long treatment for PKU patients. Still, differences exist on target blood phenylalanine (Phe) concentrations for children with PKU in different countries and treatment centers. For the first time, long-term metabolic control and child development and cognitive functioning is compared between children with mean phenylalanine concentrations under 240 μmol/L (group A), between 240 and 360 μmol/L (group B) or over 360 μmol/L (group C) during their first year of life...
December 2017: Molecular Genetics and Metabolism Reports
Youjun Xu, Jianfeng Pei, Luhua Lai
Median lethal death, LD50, is a general indicator of compound acute oral toxicity (AOT). Various in silico methods were developed for AOT prediction to reduce costs and time. In this study, we developed an improved molecular graph encoding convolutional neural networks (MGE-CNN) architecture to develop three types of high-quality AOT models: regression model (deepAOT-R), multi-classification model (deepAOTC) and multi-task (deepAOT-CR). These predictive models highly outperformed previously reported models...
October 11, 2017: Journal of Chemical Information and Modeling
Ning Liu, Qiuying Huang, Qingge Li, Dehua Zhao, Xiaole Li, Lixia Cui, Ying Bai, Yin Feng, Xiangdong Kong
BACKGROUND: Phenylketonuria (PKU), which primarily results from a deficiency of phenylalanine hydroxylase (PAH), is one of the most common inherited inborn errors of metabolism that impairs postnatal cognitive development. The incidence of various PAH variations differs by race and ethnicity. The aim of the present study was to characterize the PAH gene variants of a Han population from Northern China. METHODS: In total, 655 PKU patients and their families were recruited for this study; each proband was diagnosed both clinically and biochemically with phenylketonuria...
October 5, 2017: BMC Medical Genetics
Peng Zhai, Longshu Yang, Xiao Guo, Zhe Wang, Jiangtao Guo, Xiaoqi Wang, Huaiqiu Zhu
BACKGROUND: During the past decade, the development of high throughput nucleic sequencing and mass spectrometry analysis techniques have enabled the characterization of microbial communities through metagenomics, metatranscriptomics, metaproteomics and metabolomics data. To reveal the diversity of microbial communities and interactions between living conditions and microbes, it is necessary to introduce comparative analysis based upon integration of all four types of data mentioned above...
October 2, 2017: BMC Bioinformatics
Zhengwei Xie, Tianyu Zhang, Qi Ouyang
Motivation: One of the long-expected goals of genome-scale metabolic modelling is to evaluate the influence of the perturbed enzymes on flux distribution. Both ordinary differential equation (ODE) models and constraint-based models, like Flux balance analysis (FBA), lack the capacity to perform metabolic control analysis (MCA) for large-scale networks. Results: In this study, we developed a hyper-cube shrink algorithm (HCSA) to incorporate the enzymatic properties into the FBA model by introducing a pseudo reaction V constrained by enzymatic parameters...
September 13, 2017: Bioinformatics
Russell Perkins, Veronica Vaida
Biological membranes are a crucial aspect of living systems, controlling the organization and distribution of different chemical components. Control of membrane permeability is especially important for processes such as electron transport in metabolism and signal propagation in nerve cells. In this work, we show that the amino acid phenylalanine produces increased membrane permeability, which is likely responsible for some of the deleterious symptoms associated with high biological phenylalanine concentrations that occur with the genetic disorder phenylketonuria...
October 9, 2017: Journal of the American Chemical Society
Hardo Lilleväli, Karit Reinson, Kai Muru, Kristi Simenson, Ülle Murumets, Tõnu Möls, Katrin Õunap
The present study provides a retrospective overview of the cohort of phenylketonuria (PKU) patients in Estonia. Based on the available data, the patients clearly cluster into two distinct groups: the patients with late diagnosis and start of therapy (N = 46), who were born before 1993 when the national newborn screening programme was launched, and the screened babies (N = 48) getting their diagnoses at least in a couple of weeks after birth.Altogether 153 independent phenylalanine hydroxylase (PAH) alleles from 92 patients were analysed in the study, wherein 80% of them were carrying the p...
September 28, 2017: JIMD Reports
S Evans, A Daly, J MacDonald, A Pinto, A MacDonald
BACKGROUND: In phenylketonuria (PKU), during weaning, it is necessary to introduce a second stage phenylalanine (Phe)-free protein substitute (PS) to help meet non-Phe protein requirements. Semi-solid weaning Phe-free PS have been available for >15 years, although no long-term studies have reported their efficacy. METHODS: Retrospective data from 31 children with PKU who commenced a weaning PS were collected from clinical records from age of weaning to 2 years, on: gender; birth order; weaning age; anthropometry; blood Phe levels; age commenced and dosage of weaning PS and Phe-free infant L-amino acid formula; natural protein intake; and issues with administration of PS or food...
September 21, 2017: Journal of Human Nutrition and Dietetics: the Official Journal of the British Dietetic Association
Pongsathorn Chaiyasap, Chupong Ittiwut, Chalurmpon Srichomthong, Apiruk Sangsin, Kanya Suphapeetiporn, Vorasuk Shotelersuk
BACKGROUND: Hyperphenylalaninemia (HPA) can be classified into phenylketonuria (PKU) which is caused by mutations in the phenylalanine hydroxylase (PAH) gene, and BH4 deficiency caused by alterations in genes involved in tetrahydrobiopterin (BH4) biosynthesis pathway. Dietary restriction of phenylalanine is considered to be the main treatment of PKU to prevent irreversible intellectual disability. However, the same dietary intervention in BH4 deficiency patients is not as effective, as BH4 is also a cofactor in many neurotransmitter syntheses...
September 16, 2017: BMC Medical Genetics
Bibin G Anand, Kriti Dubey, Dolat S Shekhawat, Karunakar Kar
Excess accumulation of phenylalanine is the characteristic of untreated Phenylketonuria (PKU), a well-known genetic abnormality, which triggers several neurological, physical and developmental severities. However, the fundamental mechanism behind the origin of such diverse health problems, particularly the issue of how they are related to the build-up of phenylalanine molecules in the body, is largely unknown. Here, we show cross-seeding ability of phenylalanine fibrils that can effectively initiate an aggregation process in proteins under physiological conditions, converting native protein structures to β-sheet assembly...
September 11, 2017: Scientific Reports
Emma Medford, Dougal Julian Hare, Anja Wittkowski
Phenylketonuria (PKU) is a rare genetic disorder in which the amino acid phenylalanine cannot be sufficiently metabolised. Although a build-up of phenylalanine causes irreversible cognitive impairment, this can be prevented through a strict, lifelong diet restricted in natural protein. Despite the severe consequences of poor metabolic control, many children and adolescents have phenylalanine levels above their recommended limits. This systematic review was the first to examine studies reporting demographic and/or psychosocial influences on blood phenylalanine levels, with the aim to identify factors that were robustly linked with metabolic control...
August 25, 2017: JIMD Reports
Filippo Manti, Francesca Nardecchia, Sabrina Paci, Flavia Chiarotti, Claudia Carducci, Carla Carducci, Silvia Dalmazzone, Graziella Cefalo, Elisabetta Salvatici, Giuseppe Banderali, Vincenzo Leuzzi
Long-term cognitive outcome and treatment of adult early treated (ET)PKU patients is a main issue in PKU research. We questioned whether the intellectual development of ETPKU patients is stable and to what extent its variation may be predicted by the quality of metabolic control. The aims of the present longitudinal retrospective study were to assess in young adult ETPKU patients: i) the relationship between IQ and metabolic control during the first two decades of life; and ii) the intra- and interindividual variability in the developmental trajectory which cannot be predicted by the disease's biomarkers...
November 2017: Journal of Inherited Metabolic Disease
Jan-Niclas Schwade, Matthias Endmann, Thomas Hofmann, Stephan Rust, Jörn Oliver Sass, Frank Rutsch
A 9-month-old Turkish girl was admitted several times within 3 months to the hospital in reduced general condition and with extreme tachypnea. The patient had been diagnosed with phenylketonuria (PKU) in newborn screening and has been treated with a low phenylalanine diet and amino acid supplements. Each time an unexplained pronounced metabolic acidosis was noted, and the child was treated with sodium-bicarbonate and glucose-electrolyte infusions. The acidosis with only slightly abnormal glucose, normal lactate levels and pronounced ketonuria suggested a defect in ketone body utilization...
October 26, 2017: Journal of Pediatric Endocrinology & Metabolism: JPEM
Aaron J O'Sullivan, Sandrine Pigat, Cian O'Mahony, Michael J Gibney, Aideen I McKevitt
Artificial sweeteners are used in protein substitutes intended for the dietary management of inborn errors of metabolism (phenylketonuria, PKU) to improve the variety of medical foods available to patients and ensure dietary adherence to the prescribed course of dietary management. These patients can be exposed to artificial sweeteners from the combination of free and prescribed foods. Young children have a higher risk of exceeding acceptable daily intakes (ADI) for additives than adults, due to higher food intakes per kg body weight...
November 2017: Food Additives & Contaminants. Part A, Chemistry, Analysis, Control, Exposure & Risk Assessment
Rianne Jahja, Francjan J van Spronsen, Leo M J de Sonneville, Jaap J van der Meere, Annet M Bosch, Carla E M Hollak, M Estela Rubio-Gozalbo, Martijn C G J Brouwers, Floris C Hofstede, Maaike C de Vries, Mirian C H Janssen, Ans T van der Ploeg, Janneke G Langendonk, Stephan C J Huijbregts
Cognitive and mental health problems in individuals with the inherited metabolic disorder phenylketonuria (PKU) have often been associated with metabolic control and its history. For the present study executive functioning (EF) was assessed in 21 PKU patients during childhood (T1, mean age 10.4 years, SD = 2.0) and again in adulthood (T2, mean age 25.8 years, SD = 2.3). At T2 additional assessments of EF in daily life and mental health were performed. Childhood (i.e. 0-12 years) blood phenylalanine was significantly related to cognitive flexibility, executive motor control, EF in daily life and mental health in adulthood (i...
August 3, 2017: Behavior Genetics
Aura María Ramírez, Alexander Rodriguez-López, Andrea Ardila, Laura Beltran, Camilo Andres Patarroyo, Adelina Del Pilar Melendez, Oscar Fernando Sánchez, Carlos Javier Alméciga-Díaz
Phenylketonuria (PKU) is an autosomal recessive disorder caused by a defective phenylalanine hydroxylase (PAH), which catalyzes the hydroxylation of l-phenylalanine (l-Phe) to l-tyrosine (l-Tyr) in presence of the cofactor tetrahydrobiopterin (BH4). Defective PAH causes accumulation of phenylalanine, which has neurotoxic effects and leads to dermatological, behavioral, and neurocognitive problems. Treatments for this disease consist in life-long diets that are hard for patients to keep, or supplementation with BH4...
July 30, 2017: European Journal of Pharmaceutical Sciences
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