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Sample records for phenylketonuria pku development

  1. Development of the US English version of the phenylketonuria - quality of life (PKU-QOL) questionnaire.

    PubMed

    Jurecki, Elaina; Cunningham, Amy; Birardi, Vanessa; Gagol, Grégory; Acquadro, Catherine

    2017-03-09

    Phenylketonuria (PKU) is a rare genetic disorder caused by a defect in the metabolism of phenylalanine (PHE) resulting in elevated blood and brain PHE levels, and leading to cognitive, emotional, and psychosocial problems. The phenylketonuria - quality of life (PKU-QOL) questionnaire was the first self-administered disease-specific instrument developed to assess the impact of PKU and its treatment on the health-related quality of life (HRQL) of patients and their caregivers. Available in four versions (child, adolescent, adult and parent), the PKU-QOL was simultaneously developed and validated in seven countries [i.e., France, Germany, Italy, The Netherlands, Spain, Turkey and the United Kingdom (UK)]. The objectives of our study were to develop and linguistically validate the PKU-QOL questionnaire for use in the United States (US). The UK versions served as a basis for the development of the US English PKU-QOL questionnaire. The linguistic validation process consisted of 4 steps: 1) adaptation of the UK versions into US English by a translator native of US English and living in the US; 2) a clinician review; 3) cognitive interviews with patients and caregivers to test the appropriateness, understandability and clarity of the US translations; and 4) two proof-readings. The adaptation from UK to US English revealed the usual syntactic and idiomatic differences between the two languages, such as differences in: 1) Spelling, e.g., "dietician" (UK) vs. "dietitian" (US), or "mum" (UK) vs. "mom" (US); 2) Syntax or punctuation; and 3) Words/expressions use, e.g., "holidays" (UK) vs. "vacation" (US), or "biscuits" (UK) vs. "crackers" (US). The major issue was cultural, and consisted of using a different terminology to describe PKU treatment throughout the questionnaires. The clinician, with the patients and the caregivers, during the interviews suggested to replace "supplement and amino-acid mixture" or "supplements" with "medical formula." This wording was later changed

  2. What Are Common Symptoms of Phenylketonuria (PKU)?

    MedlinePlus

    ... Overview Condition Information What are common symptoms? How many people are affected? ... are common symptoms of phenylketonuria (PKU)? Skip sharing on social media links Share this: Page Content Children with untreated ...

  3. PKU (Phenylketonuria) in Your Baby

    MedlinePlus

    ... about 1 in 10,000 to 15,000 babies is born with PKU each year. The illness happens in all ethnic groups. But it’s more common in people who are Native American and Northern European than those who are African-American, Ashkenazi Jewish or Japanese. What causes PKU? PKU ...

  4. Muscle-directed gene therapy for phenylketonuria (PKU): Development of transgenic mice with muscle-specific phenylalanine hydroxylase expression

    SciTech Connect

    Harding, C.O.; Messing, A.; Wolff, J.A.

    1994-09-01

    Phenylketonuria (PKU) is an attractive target for gene therapy because of shortcomings in current therapy including lifelong commitment to a difficult and expensive diet, persistent mild cognitive deficits in some children despite adequate dietary therapy, and maternal PKU syndrome. Phenylalanine hydroxylase (PAH) is normally expressed only in liver, but we propose to treat PKU by introducing the gene for PAH into muscle. In order to evaluate both the safety and efficacy of this approach, we have a developed a trangenic mouse which expresses PAH in both cardiac and skeletal muscle. The transgene includes promoter and enhancer sequences from the mouse muscle creatine kinase (MCK) gene fused to the mouse liver PAH cDNA. Mice which have inherited the transgene are healthy, active, and do not exhibit any signs of muscle weakness or wasting. Ectopic PAH expression in muscle is not detrimental to the health, neurologic function, or reproduction of the mice. Pah{sup enu2} hyperphenylalaninemic mice, a model of human PAH deficiency, bred to carry the transgene have substantial PAH expression in cardiac and skeletal muscle but none in liver. Muscle PAH expression alone does not complement the hyperphenylalaninemic phenotype of Pah{sup enu2} mice. However, administration of reduced tetrahydrobiopterin to transgenic Pah{sup enu2} mice is associated with a 25% mean decrease in serum phenylalanine levels. We predict that ectopic expression of PAH in muscle along with adequate muscle supplies of reduced biopterin cofactor will decrease hyperphenylalaninemia in PKU.

  5. Phenylketonuria (PKU). ARC Q&A #101-53.

    ERIC Educational Resources Information Center

    Arc, Arlington, TX.

    This fact sheet uses a question-and-answer format to summarize what is known about phenylketonuria (PKU), an inherited metabolic disease that leads to mental retardation and other developmental disabilities if untreated in infancy. Questions and answers address the following topics: what PKU is; how PKU is inherited; the diagnosis of PKU; the…

  6. Phenylketonuria (PKU). ARC Q&A #101-53.

    ERIC Educational Resources Information Center

    Arc, Arlington, TX.

    This fact sheet uses a question-and-answer format to summarize what is known about phenylketonuria (PKU), an inherited metabolic disease that leads to mental retardation and other developmental disabilities if untreated in infancy. Questions and answers address the following topics: what PKU is; how PKU is inherited; the diagnosis of PKU; the…

  7. Pearl S. Buck and phenylketonuria (PKU).

    PubMed

    Finger, Stanley; Christ, Shawn E

    2004-03-01

    In 1921, Pearl S. Buck gave birth to a daughter, Carol, who became severely retarded and was eventually institutionalized at the Vineland Training School in New Jersey. To help pay for her daughter's care, Buck wrote The Good Earth in 1931, and then other novels and biographies about her life in China, for which she was awarded the Nobel and Pulitzer Prizes, and honored around the world. Years later, she published The Child Who Never Grew, a short piece about her daughter's retardation that also revealed her desperate search for answers and good clinical care. Asbjørn Følling distinguished phenylketonuria (PKU) from other forms of childhood retardation in the mid-1930s, and new assays and biochemical findings eventually led to ways to circumvent the devastating effects of PKU. But for Carol Buck, these advances came too late. It was not until the 1960s that physicians confirmed that her severe retardation was caused by PKU.

  8. A Current Look at Phenylketonuria (PKU).

    ERIC Educational Resources Information Center

    Fischer, Margaret

    Research was reviewed on the current status of phenylketonuria, an hereditary amino acid metabolic disorder that can cause severe mental retardation, physical complications, and emotional difficulties if not detected and treated early in childhood. A majority of the research cited was published in the 1960's. Topics covered were: discovery of…

  9. A Current Look at Phenylketonuria (PKU).

    ERIC Educational Resources Information Center

    Fischer, Margaret

    Research was reviewed on the current status of phenylketonuria, an hereditary amino acid metabolic disorder that can cause severe mental retardation, physical complications, and emotional difficulties if not detected and treated early in childhood. A majority of the research cited was published in the 1960's. Topics covered were: discovery of…

  10. Development and psychometric validation of measures to assess the impact of phenylketonuria and its dietary treatment on patients' and parents' quality of life: the phenylketonuria - quality of life (PKU-QOL) questionnaires.

    PubMed

    Regnault, Antoine; Burlina, Alberto; Cunningham, Amy; Bettiol, Esther; Moreau-Stucker, Flavie; Benmedjahed, Khadra; Bosch, Annet M

    2015-05-10

    The aim of our study was to develop and validate the first set of PKU-specific Health-related Quality of Life (HRQoL) questionnaires that: 1) were developed for patients with PKU and their parents, 2) cover the physical, emotional, and social impacts of PKU and its treatment on patients' lives, 3) are age specific (Child PKU-QOL, Adolescent PKU-QOL, Adult PKU-QOL), 4) enable the evaluation of the HRQoL of children by their parents (Parent PKU-QOL), and 5) have been cross-culturally adapted for use in seven countries (i.e. France, Germany, Italy, The Netherlands, Spain, Turkey and the UK). The PKU-QOL questionnaires were developed according to reference methods including patients', parents' and healthcare professionals' interviews; testing in a pilot study (qualitative step in six countries), and linguistic validation of the finalised pilot versions in Turkish. For finalisation and psychometric validation, the pilot versions were included in a multicentre, prospective, non-interventional, observational study conducted in 34 sites in France, Germany, Italy, The Netherlands, Spain, Turkey and the UK. Iterative multi-trait analyses were conducted. Psychometric properties were assessed (concurrent and clinical validity, internal consistency reliability and test-retest reliability). Data from 559 subjects (306 patients, 253 parents) were analysed. After finalisation, the PKU-QOL questionnaires included 40 items (Child PKU-QOL), 58 items (Adolescent PKU-QOL), 65 items (Adult PKU-QOL) and 54 items (Parent PKU-QOL), distributed in four modules: PKU symptoms, PKU in general, administration of Phe-free protein supplements and dietary protein restriction. The measurement properties of the Adolescent, Adult and Parent PKU-QOL questionnaires were overall fairly satisfactory, but weaker for the Child questionnaire. The four PKU-QOL questionnaires developed for different ages (Child PKU-QOL, Adolescent PKU-QOL, Adult PKU-QOL), and for parents of children with PKU (Parent PKU

  11. Parental strategies to help children with phenylketonuria (PKU) cope with feeling different.

    PubMed

    Zwiesele, Sheila; Bannick, Allison; Trepanier, Angela

    2015-08-01

    This study assessed feelings of differentness in children with phenylketonuria (PKU) and elicited parental coping strategies. A total of 22 parents of 7- to 12-year-old patients with PKU completed qualitative interviews, which assessed whether they think their children feel different from their peers and identified potential solution strategies. The results showed that most parents indicated their child feels different due to PKU, which is frequently triggered by situations surrounding food. PKU community involvement and educating others about PKU were perceived by parents as useful coping strategies. Talking to children about differences was frequently used but one of the least effective strategies. Extended family, clinicians, and teachers also attempted to help children cope with feeling different with varying degrees of success. We concluded that most parents perceive that their child with PKU feels different and have developed strategies to manage these feelings. However, a subset struggle with helping their child cope and may benefit from assistance from healthcare providers. © 2015 Wiley Periodicals, Inc.

  12. How Do Health Care Providers Diagnose Phenylketonuria (PKU)?

    MedlinePlus

    ... possible, most infants with the disorder developed severe intellectual disabilities. In the 1960s, researchers supported by the federal ... been almost completely eliminated as a cause of intellectual disabilities. 2 How are newborns tested for PKU? Health ...

  13. What Are Common Treatments for Phenylketonuria (PKU)?

    MedlinePlus

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  14. Mental health and social functioning in early treated Phenylketonuria: the PKU-COBESO study.

    PubMed

    Jahja, Rianne; Huijbregts, Stephan C J; de Sonneville, Leo M J; van der Meere, Jaap J; Bosch, Annet M; Hollak, Carla E M; Rubio-Gozalbo, M Estela; Brouwers, Martijn C G J; Hofstede, Floris C; de Vries, Maaike C; Janssen, Mirian C H; van der Ploeg, Ans T; Langendonk, Janneke G; van Spronsen, Francjan J

    2013-01-01

    This article presents a new Dutch multicenter study ("PKU-COBESO") into cognitive and behavioral sequelae of early and continuously treated Phenylketonuria (PKU) patients. Part of the study sample will consist of young adult PKU patients who have participated in a large neuropsychological study approximately 10 years ago, when they were 7-to-15-year-olds (Huijbregts et al., 2002 [1]). Their neurocognitive development will be mapped in association with their earlier and continued metabolic history, taking into account possible changes in, for instance, medication. A second part of the sample will consist of PKU patients between the ages of 7 and approximately 40 years (i.e., born in or after 1974, when neonatal screening was introduced in The Netherlands), who have not participated in the earlier neuropsychological study. Again, their cognitive functioning will be related to their metabolic history. With respect to aspects of cognition, there will be an emphasis on executive functioning. The concept of executive functioning will however be extended with further emphasis on the impact of cognitive deficits on the daily lives of PKU patients, aspects of social cognition, social functioning, and behavior/mental health (i.e., COgnition, BEhavior, SOcial functioning: COBESO). In addition to a description of the PKU-COBESO study, some preliminary results with respect to mental health and social functioning will be presented in this article. Thirty adult PKU patients (mean age 27.8, SD 6.4) and 23 PKU patients under the age of 18 years (mean age 11.0, SD 3.3) were compared to 14 (mean age 26.9 years, SD 5.9) and 7 matched controls (mean age 10.5, SD 2.6) respectively, with respect to their scores on the Adult Self-Report or Child Behavior Checklist (measuring mental health problems) and the Social Skills Checklist or Social Skills Rating System (measuring social skills). Whereas there were very few significant group differences (except for mental health problems in the

  15. Education of Students with Phenylketonuria (PKU): Information for Teachers, Administrators and Other School Personnel.

    ERIC Educational Resources Information Center

    National Inst. of Child Health and Human Development (NIH), Bethesda, MD.

    This booklet summarizes current knowledge about phenylketonuria (PKU), an inherited condition that results in severe mental retardation if untreated, and discusses the psychoeducational implications of the condition. The introduction stresses the importance of early diagnosis (during the first days of life) and the effectiveness of a diet that…

  16. Phenylketonuria

    MedlinePlus

    ... without the ability to properly break down an amino acid called phenylalanine. Causes Phenylketonuria (PKU) is inherited, which ... which is needed to break down the essential amino acid phenylalanine. Phenylalanine is found in foods that contain ...

  17. Cognitive Outcomes in Early-Treated Adults With Phenylketonuria (PKU): A Comprehensive Picture Across Domains

    PubMed Central

    2017-01-01

    Objective: Phenylketonuria (PKU) is an inherited metabolic disease which affects cognitive functions due to an inability to metabolize phenylalanine which leads to the accumulation of toxic by-products (Phe) in the brain. PKU can be effectively treated with a low phenylalanine diet, but some cognitive deficits remain. Studies have reported impairments, especially for processing speed and executive functions, but there is a lack of comprehensive assessment across cognitive domains. Moreover, it is important to establish outcomes in early treated adults with PKU (AwPKU) who have better metabolic control than groups previously reported in the literature. Method: We tested 37 AwPKU with an unprecedented number of tasks (N = 28) and measures (N = 44) and compared results with 30 controls matched for age and education. Results: We found (a) group impairments, particularly in tasks tapping speed of processing and complex executive functions; (b) high variability across participants, with a sizable number of AwPKU with completely normal performance (about 38%); (c) but also a sizable number of participants who were clearly impaired (about 24%); and (d) good performance in tasks tapping verbal learning, verbal memory and orthographic processing, indicating no generalized learning impairment. Conclusion: Our results indicate good outcomes, but also that deficits are still present with current treatment policies. PMID:28080075

  18. Cognitive outcomes in early-treated adults with phenylketonuria (PKU): A comprehensive picture across domains.

    PubMed

    Palermo, Liana; Geberhiwot, Tarekegn; MacDonald, Anita; Limback, Ellie; Hall, S Kate; Romani, Cristina

    2017-03-01

    Phenylketonuria (PKU) is an inherited metabolic disease which affects cognitive functions due to an inability to metabolize phenylalanine which leads to the accumulation of toxic by-products (Phe) in the brain. PKU can be effectively treated with a low phenylalanine diet, but some cognitive deficits remain. Studies have reported impairments, especially for processing speed and executive functions, but there is a lack of comprehensive assessment across cognitive domains. Moreover, it is important to establish outcomes in early treated adults with PKU (AwPKU) who have better metabolic control than groups previously reported in the literature. We tested 37 AwPKU with an unprecedented number of tasks (N = 28) and measures (N = 44) and compared results with 30 controls matched for age and education. We found (a) group impairments, particularly in tasks tapping speed of processing and complex executive functions; (b) high variability across participants, with a sizable number of AwPKU with completely normal performance (about 38%); (c) but also a sizable number of participants who were clearly impaired (about 24%); and (d) good performance in tasks tapping verbal learning, verbal memory and orthographic processing, indicating no generalized learning impairment. Our results indicate good outcomes, but also that deficits are still present with current treatment policies. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  19. Pharmacologic inhibition of L-tyrosine degradation ameliorates cerebral dopamine deficiency in murine phenylketonuria (PKU)

    PubMed Central

    Harding, Cary O.; Winn, Shelley R.; Gibson, K. Michael; Arning, Erland; Bottiglieri, Teodoro; Grompe, Markus

    2014-01-01

    Summary Monoamine neurotransmitter deficiency has been implicated in the etiology of neuropsychiatric symptoms associated with chronic hyperphenylalaninemia in phenylketonuria (PKU). Two proposed explanations for neurotransmitter deficiency in PKU include first, that chronically elevated blood L-phenylalanine (Phe) inhibits the transport of L-tyrosine (Tyr) and L-tryptophan (Trp), the substrates for dopamine and serotonin synthesis respectively, into brain. In the second hypothesis, elevated Phe competitively inhibits brain tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities, the rate limiting steps in dopamine and serotonin synthesis. Dietary supplementation with large neutral amino acids (LNAA) including Tyr and Trp has been recommended for individuals with chronically elevated blood Phe in an attempt to restore amino acid and monoamine homeostasis in brain. As a potential alternative treatment approach, we demonstrate that pharmacologic inhibition of Tyr degradation through oral administration of nitisinone (NTBC) yielded sustained increases in blood and brain Tyr, decreased blood and brain Phe, and consequently increased dopamine synthesis in a murine model of PKU. Our results suggest that Phe-mediated inhibition of TH activity is the likely mechanism of impaired dopamine synthesis in PKU. Pharmacologic inhibition of Tyr degradation may be a promising adjunct therapy for CNS monoamine neurotransmitter deficiency in hyperphenylalaninemic individuals with PKU. PMID:24487571

  20. Pharmacologic inhibition of L-tyrosine degradation ameliorates cerebral dopamine deficiency in murine phenylketonuria (PKU).

    PubMed

    Harding, Cary O; Winn, Shelley R; Gibson, K Michael; Arning, Erland; Bottiglieri, Teodoro; Grompe, Markus

    2014-09-01

    Monoamine neurotransmitter deficiency has been implicated in the etiology of neuropsychiatric symptoms associated with chronic hyperphenylalaninemia in phenylketonuria (PKU). Two proposed explanations for neurotransmitter deficiency in PKU include first, that chronically elevated blood L-phenylalanine (Phe) inhibits the transport of L-tyrosine (Tyr) and L-tryptophan (Trp), the substrates for dopamine and serotonin synthesis respectively, into brain. In the second hypothesis, elevated Phe competitively inhibits brain tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities, the rate limiting steps in dopamine and serotonin synthesis. Dietary supplementation with large neutral amino acids (LNAA) including Tyr and Trp has been recommended for individuals with chronically elevated blood Phe in an attempt to restore amino acid and monoamine homeostasis in brain. As a potential alternative treatment approach, we demonstrate that pharmacologic inhibition of Tyr degradation through oral administration of nitisinone (NTBC) yielded sustained increases in blood and brain Tyr, decreased blood and brain Phe, and consequently increased dopamine synthesis in a murine model of PKU. Our results suggest that Phe-mediated inhibition of TH activity is the likely mechanism of impaired dopamine synthesis in PKU. Pharmacologic inhibition of Tyr degradation may be a promising adjunct therapy for CNS monoamine neurotransmitter deficiency in hyperphenylalaninemic individuals with PKU.

  1. Phenylketonuria (PKU)

    MedlinePlus

    ... Disorder (ASD) Intellectual and Developmental Disabilities (IDDs) Newborn Screening NICHD News and Spotlights Getting to Know the New NICHD Director Neuroscience Research Resources NIH Scientists Combine ...

  2. Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAHenu2 mouse model of PKU.

    PubMed

    Durrer, Katherine E; Allen, Michael S; Hunt von Herbing, Ione

    2017-01-01

    Phenylketonuria (PKU) is a genetic disease characterized by the inability to convert dietary phenylalanine to tyrosine by phenylalanine hydroxylase. Given the importance of gut microbes in digestion, a genetically engineered microbe could potentially degrade some ingested phenylalanine from the diet prior to absorption. To test this, a phenylalanine lyase gene from Anabaena variabilis (AvPAL) was codon-optimized and cloned into a shuttle vector for expression in Lactobacillus reuteri 100-23C (pHENOMMenal). Functional expression of AvPAL was determined in vitro, and subsequently tested in vivo in homozygous PAHenu2 (PKU model) mice. Initial trials of two PAHenu2 homozygous (PKU) mice defined conditions for freeze-drying and delivery of bacteria. Animals showed reduced blood phe within three to four days of treatment with pHENOMMenal probiotic, and blood phe concentrations remained significantly reduced (P < 0.0005) compared to untreated controls during the course of experiments. Although pHENOMMenal probiotic could be cultured from fecal samples at four months post treatment, it could no longer be cultivated from feces at eight months post treatment, indicating eventual loss of the microbe from the gut. Preliminary screens during experimentation found no immune response to AvPAL. Collectively these studies provide data for the use of a genetically engineered probiotic as a potential treatment for PKU.

  3. Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAHenu2 mouse model of PKU

    PubMed Central

    Durrer, Katherine E.; Allen, Michael S.; Hunt von Herbing, Ione

    2017-01-01

    Phenylketonuria (PKU) is a genetic disease characterized by the inability to convert dietary phenylalanine to tyrosine by phenylalanine hydroxylase. Given the importance of gut microbes in digestion, a genetically engineered microbe could potentially degrade some ingested phenylalanine from the diet prior to absorption. To test this, a phenylalanine lyase gene from Anabaena variabilis (AvPAL) was codon-optimized and cloned into a shuttle vector for expression in Lactobacillus reuteri 100-23C (pHENOMMenal). Functional expression of AvPAL was determined in vitro, and subsequently tested in vivo in homozygous PAHenu2 (PKU model) mice. Initial trials of two PAHenu2 homozygous (PKU) mice defined conditions for freeze-drying and delivery of bacteria. Animals showed reduced blood phe within three to four days of treatment with pHENOMMenal probiotic, and blood phe concentrations remained significantly reduced (P < 0.0005) compared to untreated controls during the course of experiments. Although pHENOMMenal probiotic could be cultured from fecal samples at four months post treatment, it could no longer be cultivated from feces at eight months post treatment, indicating eventual loss of the microbe from the gut. Preliminary screens during experimentation found no immune response to AvPAL. Collectively these studies provide data for the use of a genetically engineered probiotic as a potential treatment for PKU. PMID:28520731

  4. High dose sapropterin dihydrochloride therapy improves monoamine neurotransmitter turnover in murine phenylketonuria (PKU).

    PubMed

    Winn, Shelley R; Scherer, Tanja; Thöny, Beat; Harding, Cary O

    2016-01-01

    Central nervous system (CNS) deficiencies of the monoamine neurotransmitters, dopamine and serotonin, have been implicated in the pathophysiology of neuropsychiatric dysfunction in phenylketonuria (PKU). Increased brain phenylalanine concentration likely competitively inhibits the activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), the rate limiting steps in dopamine and serotonin synthesis respectively. Tetrahydrobiopterin (BH4) is a required cofactor for TH and TPH activity. Our hypothesis was that treatment of hyperphenylalaninemic Pah(enu2/enu2) mice, a model of human PKU, with sapropterin dihydrochloride, a synthetic form of BH4, would stimulate TH and TPH activities leading to improved dopamine and serotonin synthesis despite persistently elevated brain phenylalanine. Sapropterin (20, 40, or 100mg/kg body weight in 1% ascorbic acid) was administered daily for 4 days by oral gavage to Pah(enu2/enu2) mice followed by measurement of brain biopterin, phenylalanine, tyrosine, tryptophan and monoamine neurotransmitter content. A significant increase in brain biopterin content was detected only in mice that had received the highest sapropterin dose, 100mg/kg. Blood and brain phenylalanine concentrations were unchanged by sapropterin therapy. Sapropterin therapy also did not alter the absolute amounts of dopamine and serotonin in brain but was associated with increased homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), dopamine and serotonin metabolites respectively, in both wild type and Pah(enu2/enu2) mice. Oral sapropterin therapy likely does not directly affect central nervous system monoamine synthesis in either wild type or hyperphenylalaninemic mice but may stimulate synaptic neurotransmitter release and subsequent metabolism. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Are neuropsychological impairments in children with early-treated phenylketonuria (PKU) related to white matter abnormalities or elevated phenylalanine levels?

    PubMed

    Anderson, Peter J; Wood, Stephen J; Francis, Dorothy E; Coleman, Lee; Anderson, Vicki; Boneh, Avihu

    2007-01-01

    This study aimed to enhance our understanding of neuropsychological functioning in children with early-treated phenylketonuria (PKU) and assess the relative impact of white matter abnormalities (WMA) and neurotransmitter deficiencies on cognitive functions in this population. The study consisted of 33 children with early-treated PKU and 34 healthy control children aged between 7 to 18 years. All children had a neuropsychological evaluation that included measures of general intelligence, attention, processing speed, memory and learning, executive function, and academic achievement. Children in the PKU group also had a magnetic resonance (MR) brain scan. When compared with the control group, the PKU group exhibited global cognitive impairment including lower IQ, attention problems, slow information processing, reduced learning capacity, mild executive impairments, and educational difficulties. Children in the PKU group with extensive WMA (n = 14) displayed significant impairments across all cognitive domains. Metabolic control correlated weakly to moderately with attention, executive, and memory/learning factors. Within the PKU group, regressions revealed that executive function and attention factors were independently related to severity of WM pathology and age, while the memory and learning factor was independently related to metabolic control and age. It is concluded that children with early-treated PKU exhibit a global pattern of impairment, with a particular deficit in processing speed. WM pathology extending into frontal and subcortical regions correlates with the greatest deficits and a profile of impairment consistent with diffuse WM damage. Our findings also offer some support for dopamine depletion in the prefrontal cortex, however adverse consequences as a result of norepinephrine and serotonin deficiencies should not be discounted.

  6. Social-cognitive functioning and social skills in patients with early treated phenylketonuria: a PKU-COBESO study.

    PubMed

    Jahja, Rianne; van Spronsen, Francjan J; de Sonneville, Leo M J; van der Meere, Jaap J; Bosch, Annet M; Hollak, Carla E M; Rubio-Gozalbo, M Estela; Brouwers, Martijn C G J; Hofstede, Floris C; de Vries, Maaike C; Janssen, Mirian C H; van der Ploeg, Ans T; Langendonk, Janneke G; Huijbregts, Stephan C J

    2016-05-01

    Early treatment of phenylketonuria (ET-PKU) prevents mental retardation, but many patients still show cognitive and mood problems. In this study, it was investigated whether ET-PKU-patients have specific phenylalanine (Phe-)related problems with respect to social-cognitive functioning and social skills. Ninety five PKU-patients (mean age 21.6 ± 10.2 years) and 95 healthy controls (mean age 19.6 ± 8.7 years) were compared on performance of computerized and paper-and-pencil tasks measuring social-cognitive abilities and on parent- and self-reported social skills, using multivariate analyses of variance, and controlling for general cognitive ability (IQ-estimate). Further comparisons were made between patients using tetrahydrobiopterin (BH4, N = 30) and patients not using BH4. Associations with Phe-levels on the day of testing, during childhood, during adolescence and throughout life were examined. PKU-patients showed poorer social-cognitive functioning and reportedly had poorer social skills than controls (regardless of general cognitive abilities). Quality of social-cognitive functioning was negatively related to recent Phe-levels and Phe-levels between 8 and 12 years for adolescents with PKU. Quality of social skills was negatively related to lifetime phenylalanine levels in adult patients, and specifically to Phe-levels between 0 and 7, and between 8 and 12 years. There were no differences with respect to social outcome measures between the BH4 and non-BH4 groups. PKU-patients have Phe-related difficulties with social-cognitive functioning and social skills. Problems seem to be more evident among adolescents and adults with PKU. High Phe-levels during childhood and early adolescence seem to be of greater influence than current and recent Phe-levels for these patients.

  7. [Evaluation of physical development in children with classical phenylketonuria].

    PubMed

    Bushueva, T V; Borovik, T E; Ladodo, K S; Kuzenkova, L M; Maslova, O I; Gevorkyan, A K

    2015-01-01

    Classical phenylketonuria (PKU) is hereditary disease, which is based on the disturbance of phenylalanine conversion to tyrosine. The basic treatment of PKU is low phenylalanine diet. Prolonged restriction of natural protein may have a negative impact to PKU patient growth and physical development. The objective was to evaluate the physical development of patients with classical PKU at birth and on the diet based on the products with different chemical composition without phenylalanine. 257 PKU patients have been examined with the computer program "WHO Anthroplus 2009". All patient were born at term. Z-score of body weight, height and body mass index (BMI) to age has been retrospectively estimated. Patients were divided into 2 groups: group 1--101 children born in 1980-1993 were fed by unadapted specialty products based on protein hydrolyzate with restricted phenylalanine, and group 2--156 children born in 1995-2012 were fed by contemporary amino acid mixtures without phenylalanine. All newborn PKU patients had the middle for age Z-score of weight and BMI, 21% of neonates had high Z-score growth. Before the diet therapy BMI Z-score was normal in 84.1% patients in group 1 and 87.2% patients of group 2. After 6 mo of treatment with low phenylalanine diet the number of patient with normal BMI Z-score was 71.3% in group 1 against 95.6% in group 2. Thus, using of modern amino acid mixtures without phenylalanine, enriched with essential nutrients can promote the normal physical development of PKU patients.

  8. Phenylketonuria

    NASA Astrophysics Data System (ADS)

    Lane, J. D.; Neuhoff, V.

    1980-05-01

    Phenylketonuria is a genetic defect that leads to imbecility, if the diagnosis is not made directly after birth. Since the development of imbecility can be almost totally halted by suitable dietary treatment, phenylketonuria is of more interest to neurochemists than to clinicians. This genetic defect is not known to occur in animals. It is therefore necessary to develop suitable models for neurochemical analysis. Most successful is the simultaneous application to developing rats of α-methyl-phenylalanine (an inhibitor of phenylalanine hydroxylase), together with phenylalanine. With this treatment it is possible to induce changes in the central nervous system which are surprisingly similar to those found in patients with phenylketonuria. This model is therefore of great importance in the analyses of the disturbances of metabolism, which finally causes the severe defects in normal brain function.

  9. Evaluation of quality of life and description of the sociodemographic state in adolescent and young adult patients with phenylketonuria (PKU).

    PubMed

    Simon, Eva; Schwarz, Martin; Roos, Judith; Dragano, Nico; Geraedts, Max; Siegrist, Johannes; Kamp, Gudrun; Wendel, Udo

    2008-03-26

    Normal intellectual and personal development can be expected in early-diagnosed and treated PKU patients. Aim of the study was to analyse quality of life and social status, which are important parameters for an overall estimation of success of treatment apart from intellectual outcome in adult PKU patients. 67 patients completed a questionnaire on quality of life and social status. Data was compared to the German census on an age matched control collective. Quality of life measured with the Profile of Quality of Life in the Chronically Ill (PLC) revealed mean values for capacity of performance in the patient group in the same range as in the control collective. The analysis of the social state of PKU patients revealed a tendency towards lower or delayed autonomy, and a low rate of forming normal adult relationships in which to have children. Schooling and professional career corresponded approximately to the control collective. Though every chronic disorder must be regarded as restraining, it shows that PKU does not preclude healthy emotional adjustment when the disease is diagnosed early and treated well.

  10. Phenylketonuria and maternal phenylketonuria.

    PubMed

    Purnell, H

    2001-07-01

    Phenylketonuria is a genetic disease affecting 1:10,000 to 14,000 live births. In NSW there is an average of nine cases diagnosed each year (Dietitians Working Party 1996). This paper discusses the management of phenylketonuria, and in particular the value of breastfeeding, complemented with a low phenylalanine infant formula, in facilitating easier maintenance of satisfactory phenylalanine blood levels. The 'diet for life' approach to managing phenylketonuria is to avoid long-term neurological deficits and, in particular, the risk that maternal PKU, which is not under strict dietary control, will have adverse effects on infants born of mothers with the disease. There have been 31 successful pregnancies to 1997 managed by the Nutrition and Dietetics Department of The Children's Hospital at Westmead, Sydney. The Maternal PKU diet is presented with the case of a client with phenylketonuria who has achieved two normal pregnancies and breastfed her second child for six months.

  11. Hepatitis virus protein X-Phenylalanine Hydroxylase fusion proteins identified in PKU mice treated with AAV-WPRE vectors

    USDA-ARS?s Scientific Manuscript database

    Utilizing the Pahenu2 mouse model for phenylketonuria (PKU), we developed an improved expression vector containing the Woodchuck Hepatitis Virus post-transcriptional regulatory element inserted into a rAAV-mPAH construct (rAAV-mPAH-WPRE) for treatment of PKU. Following portal vein delivery of these ...

  12. Learning about Phenylketonuria (PKU)

    MedlinePlus

    ... Resources NHGRI-Related News Journal Articles from NHGRI Social Media Careers Educational Programs Health Professional Education Intramural Training Office Online Careers & Training Resources Training ...

  13. What Is Phenylketonuria (PKU)?

    MedlinePlus

    ... have it? For more information... Acknowledgments Concept 15 : DNA and proteins are key molecules of the cell nucleus. Learn the basic chemistry of DNA and proteins. Concept 27 : Mutations are changes in ...

  14. Phenylketonuria: An Inborn Error of Phenylalanine Metabolism

    PubMed Central

    Williams, Robin A; Mamotte, Cyril DS; Burnett, John R

    2008-01-01

    Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism resulting from deficiency of phenylalanine hydroxylase (PAH). Most forms of PKU and hyperphenylalaninaemia (HPA) are caused by mutations in the PAH gene on chromosome 12q23.2. Untreated PKU is associated with an abnormal phenotype which includes growth failure, poor skin pigmentation, microcephaly, seizures, global developmental delay and severe intellectual impairment. However, since the introduction of newborn screening programs and with early dietary intervention, children born with PKU can now expect to lead relatively normal lives. A better understanding of the biochemistry, genetics and molecular basis of PKU, as well as the need for improved treatment options, has led to the development of new therapeutic strategies. PMID:18566668

  15. Is overweight an issue in phenylketonuria?

    PubMed

    Rocha, Júlio C; MacDonald, Anita; Trefz, Friedrich

    2013-01-01

    Dietary treatment may be associated with an increased risk of obesity in phenylketonuria (PKU). The earliest studies describe a tendency for overweight in PKU, but not all recent publications confirm this, although there are an increasing number of studies describing increased obesity in female patients with PKU. There is little data describing the metabolic consequences of obesity in PKU. It is difficult to interpret and compare published results due to variable patient age, differing dietary treatment approaches, poor treatment adherence, inconsistencies in metabolic control achieved, variable criteria used to classify overweight. There is also a lack of comparison with normal population data which is widely variable between countries. Generally in PKU it is unknown if obesity etiology is a result of the underlying condition, a treatment consequence, or an outcome of inadequate metabolic control. Differences in treatment strategies, target ranges for blood phenylalanine concentrations and severity of PKU can alter nutritional intakes and dietary experiences which ultimately modulate the course of overweight development. It is clear further investigation is required. Treating overweight and obesity in the general population is difficult and no studies have described the impact of obesity treatment strategies in PKU. However, the PKU management team has an important role in monitoring nutritional status and preventing overweight and obesity. It is important that PKU treatment attends to the general aspects of nutrition, feeding behavior and exercise in order to prevent the development of overweight in these individuals. © 2013.

  16. Classic Phenylketonuria: Diagnosis Through Heterozygote Detection

    ERIC Educational Resources Information Center

    Griffin, Robert F.; Elsas, Louis J.

    1975-01-01

    In an attempt to improve the identification of the asymptomatic carrier of classic phenylketonuria (PKU) 59 male and female normal control Ss were differentiated from 18 males and females heterozgous for PKU. (DB)

  17. Classic Phenylketonuria: Diagnosis Through Heterozygote Detection

    ERIC Educational Resources Information Center

    Griffin, Robert F.; Elsas, Louis J.

    1975-01-01

    In an attempt to improve the identification of the asymptomatic carrier of classic phenylketonuria (PKU) 59 male and female normal control Ss were differentiated from 18 males and females heterozgous for PKU. (DB)

  18. Practical aspects of recruitment and retention in clinical trials of rare genetic diseases: the phenylketonuria (PKU) experience.

    PubMed

    DeWard, Stephanie J; Wilson, Ashley; Bausell, Heather; Volz, Ashley S; Mooney, Kimberly

    2014-02-01

    Bringing treatments for rare genetic diseases to patients requires clinical research. Despite increasing activism from patient support and advocacy groups to increase access to clinical research studies, connecting rare disease patients with the clinical research opportunities that may help them has proven challenging. Chief among these challenges are the low incidence of these diseases resulting in a very small pool of known patients with a particular disease, difficulty of diagnosing rare genetic diseases, logistical issues such as long distances to the nearest treatment center, and substantial disease burden leading to loss of independence. Using clinical studies of phenylketonuria as an example, this paper discusses how, based on the authors' collective experience, partnership among clinicians, patients, study coordinators, genetic counselors, dietitians, industry, patient support groups, and families can help overcome the challenges of recruiting and retaining patients in rare disease clinical trials. We discuss specific methods of collaboration, communication, and education as part of a long-term effort to build a community committed to advancing the medical care of patients with rare genetic diseases. By talking to patients and families regularly about research initiatives and taking steps to make study participation as easy as possible, rare disease clinic staff can help ensure adequate study enrollment and successful study completion.

  19. Nutritional Management of Phenylketonuria

    PubMed Central

    MacLeod, Erin L.; Ney, Denise M.

    2010-01-01

    Phenylketonuria (PKU) is caused by deficient activity of the enzyme phenylalanine hydroxylase, needed to convert the essential amino acid (AA) phenylalanine (phe) to tyrosine. In order to prevent neurological damage, lifelong adherence to a low-phe diet that is restricted in natural foods and requires ingestion of a phe-free AA formula to meet protein needs is required. The goal of nutritional management for those with PKU is to maintain plasma phe concentrations that support optimal growth, development, and mental functioning while providing a nutritionally complete diet. This paper reviews developing a lifelong dietary prescription for those with PKU, outcomes of nutritional management, compliance with the low-phe diet across the life cycle, and new options for nutritional management. An individualized dietary prescription is needed to meet nutrient requirements, and the adequacy of phe intake is monitored with assessment of blood phe levels. Elevated phe concentrations may occur due to illness, excessive or inadequate phe intake, or inadequate intake of AA formula. Although normal growth and development occurs with adherence to the low-phe diet, it is important to monitor vitamin, mineral and essential fatty acid status, especially in those who do not consume sufficient AA formula. Given the growing population of adults with PKU, further research is needed to understand the risks for developing osteoporosis and cardiovascular disease. There are promising new options to liberalize the diet and improve metabolic control such as tetrahydrobiopterin therapy or supplementation with large neutral AAs. Moreover, foods made with glycomacropeptide, an intact protein that contains minimal phe, improves the PKU diet by offering a palatable alternative to AA formula. In summary, continued efforts are needed to overcome the biggest challenge to living with PKU – lifelong adherence to the low-phe diet. PMID:22475869

  20. Requirements for a minimum standard of care for phenylketonuria: the patients’ perspective

    PubMed Central

    2013-01-01

    Phenylketonuria (PKU, ORPHA716) is an inherited disorder that affects about one in every 10,000 children born in Europe. Early and continuous application of a modified diet is largely successful in preventing the devastating brain damage associated with untreated PKU. The management of PKU is inconsistent: there are few national guidelines, and these tend to be incomplete and implemented sporadically. In this article, the first-ever pan- European patient/carer perspective on optimal PKU care, the European Society for Phenylketonuria and Allied Disorders (E.S.PKU) proposes recommendations for a minimum standard of care for PKU, to underpin the development of new pan-European guideline for the management of PKU. New standards of best practice should guarantee equal access to screening, treatment and monitoring throughout Europe. Screening protocols and interpretation of screening results should be standardised. Experienced Centres of Expertise are required, in line with current European Union policy, to guarantee a defined standard of multidisciplinary treatment and care for all medical and social aspects of PKU. Women of childbearing age require especially intensive management, due to the risk of severe risks to the foetus conferred by uncontrolled PKU. All aspects of treatment should be reimbursed to ensure uniform access across Europe to guideline-driven, evidence-based care. The E.S.PKU urges PKU healthcare professionals caring for people with PKU to take the lead in developing evidence based guidelines on PKU, while continuing to play an active role in serving as the voice of patients and their families, whose lives are affected by the condition. PMID:24341788

  1. Nutritional issues in treating phenylketonuria.

    PubMed

    Feillet, François; Agostoni, Carlo

    2010-12-01

    A phenylalanine (Phe)-restricted diet is the mainstay of phenylketonuria (PKU) treatment, and, in recent years, the nutritional management of PKU has become more complex in order to optimize patients' growth, development and diet compliance. Dietary restriction of Phe creates a diet similar to a vegan diet, and many of the nutritional concerns and questions applicable to vegans who wish to avoid animal products are also relevant to patients with PKU. Owing to their nutritional characteristics, breast milk and breastfeeding should be given greater consideration as a useful food in patients with PKU and in those with other inborn errors of metabolism. Further key issues for consideration include the quality of the available amino acid substitutes, the neurotrophic and neuroprotective effects of added long-chain polyunsaturated fatty acids (e.g. docosahexaenoic acid), micronutrient deficiencies, bone disease and antioxidant status. Long-term dietary guidance and monitoring of the nutritional status of patients with PKU should be part of a follow-up programme that continues for life.

  2. PKU (Phenylketonuria) in Your Baby

    MedlinePlus

    ... unit (NICU) Birth defects & other health conditions Loss & grief Tools & Resources Frequently asked health questions Ask our ... experts Calculating your due date Ovulation calendar Order bereavement materials News Moms Need Blog News & Media News ...

  3. Progress toward cell-directed therapy for phenylketonuria

    PubMed Central

    Harding, CO

    2009-01-01

    Phenylketonuria (PKU) is one of the most common inborn errors of metabolism with an annual incidence of approximately 1:16,000 live births in North America. Contemporary therapy relies upon lifelong dietary protein restriction and supplementation with phenylalanine-free medical foods. This therapy is expensive and unpalatable; dietary compliance is difficult to maintain throughout life. Non-adherence to the diet is associated with learning disabilities, adult-onset neurodegenerative disease, and maternal PKU syndrome. The fervent dream of many individuals with PKU is a more permanent cure for this disease. This paper will review ongoing efforts to develop viable cell-directed therapies, in particular cell transplantation and gene therapy, for the treatment of PKU. PMID:18498375

  4. Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations.

    PubMed

    Schuck, Patrícia Fernanda; Malgarin, Fernanda; Cararo, José Henrique; Cardoso, Fabiola; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2015-09-01

    Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism caused by the deficiency of phenylalanine hydroxylase. This deficiency leads to the accumulation of Phe and its metabolites in tissues and body fluids of PKU patients. The main signs and symptoms are found in the brain but the pathophysiology of this disease is not well understood. In this context, metabolic alterations such as oxidative stress, mitochondrial dysfunction, and impaired protein and neurotransmitters synthesis have been described both in animal models and patients. This review aims to discuss the main metabolic disturbances reported in PKU and relate them with the pathophysiology of this disease. The elucidation of the pathophysiology of brain damage found in PKU patients will help to develop better therapeutic strategies to improve quality of life of patients affected by this condition.

  5. Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations

    PubMed Central

    Schuck, Patrícia Fernanda; Malgarin, Fernanda; Cararo, José Henrique; Cardoso, Fabiola; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2015-01-01

    Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism caused by the deficiency of phenylalanine hydroxylase. This deficiency leads to the accumulation of Phe and its metabolites in tissues and body fluids of PKU patients. The main signs and symptoms are found in the brain but the pathophysiology of this disease is not well understood. In this context, metabolic alterations such as oxidative stress, mitochondrial dysfunction, and impaired protein and neurotransmitters synthesis have been described both in animal models and patients. This review aims to discuss the main metabolic disturbances reported in PKU and relate them with the pathophysiology of this disease. The elucidation of the pathophysiology of brain damage found in PKU patients will help to develop better therapeutic strategies to improve quality of life of patients affected by this condition. PMID:26425393

  6. How Is PKU Monitored?

    MedlinePlus

    Skip to main content. PKU Clinic - University of Washington, Seattle Home | Contact Us | Site Map PKU Management For Health Care Providers RECIPES about pku UW PKU Clinic News & Events What is PKU? What is the diet ...

  7. The birth prevalence of PKU in populations of European, South Asian and sub-Saharan African ancestry living in South East England.

    PubMed

    Hardelid, P; Cortina-Borja, M; Munro, A; Jones, H; Cleary, M; Champion, M P; Foo, Y; Scriver, C R; Dezateux, C

    2008-01-01

    Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism (OMIM 261600). Treatment with a low-phenylalanine diet following early ascertainment by newborn screening prevents impaired cognitive development, the major disease phenotype in PKU. The overall birth prevalence of PKU in European, Chinese and Korean populations is approximately 1/10,000. Since the human PAH locus contains PKU-causing alleles and polymorphic core haplotypes that describe and corroborate an out-of-Africa range expansion in modern human populations, it is of interest to know the prevalence of PKU in different ethnic groups with diverse geographical origin. We estimated PKU prevalence in South East England, where a sizeable proportion of the population are of Sub-Saharan African or South Asian ancestry. Over the period 1994 to 2004 167 children were diagnosed with PKU. Using birth registration and census data to derive denominators, PKU birth prevalence per 10,000 live births (95% Bayesian credible intervals) was estimated to be 1.14 (0.96-1.33) among white, 0.11 (0.02-0.37) among black, and 0.29 (0.10-0.63) among Asian ethnic groups. This suggests that PKU is up to an order of magnitude less prevalent in populations with Sub-Saharan African and South Asian ancestry that have migrated to the UK.

  8. Neuropsychology of Early-Treated Phenylketonuria: Specific Executive Function Deficits.

    ERIC Educational Resources Information Center

    Welsh, Marilyn C.; And Others

    1990-01-01

    Early-treated phenylketonuria (PKU) children and unaffected peers were evaluated on four executive function (EF) tasks and one nonexecutive task. The PKU children scored lower than unaffected children on EF tasks, but not on the nonexecutive task. The PKU children's composite EF score was correlated with concurrent and mean lifetime phenylalanine…

  9. Neuropsychology of Early-Treated Phenylketonuria: Specific Executive Function Deficits.

    ERIC Educational Resources Information Center

    Welsh, Marilyn C.; And Others

    1990-01-01

    Early-treated phenylketonuria (PKU) children and unaffected peers were evaluated on four executive function (EF) tasks and one nonexecutive task. The PKU children scored lower than unaffected children on EF tasks, but not on the nonexecutive task. The PKU children's composite EF score was correlated with concurrent and mean lifetime phenylalanine…

  10. State-of-the-art 2003 on PKU gene therapy.

    PubMed

    Ding, Zhaobing; Harding, Cary O; Thöny, Beat

    2004-01-01

    Phenylketonuria (or PKU) is a well-known and widespread genetic disease for which many countries perform newborn screening, and life-long dietary restriction is still the ultimate and effective therapy. However, the diet is complicated, unpalatable, and expensive. The long-term effects of diet discontinuation in adults, except for the serious adverse effects of maternal hyperphenylalaninemia upon the developing fetus, have not been systematically studied, but cognitive decline and neurologic abnormalities have been anecdotally reported. Thus, alternative approaches for PKU therapy, including gene therapy, must be further explored. Here we summarize past present nonviral and viral gene transfer approaches, both in vitro studies and preclinical animal trials, to delivering the PAH gene into liver or other organs as potential alternatives to life-long phenylalanine-restricted dietary therapy.

  11. Genetic interaction between pku300 and fbn2b controls endocardial cell proliferation and valve development in zebrafish.

    PubMed

    Wang, Xu; Yu, Qingming; Wu, Qing; Bu, Ye; Chang, Nan-Nan; Yan, Shouyu; Zhou, Xiao-Hai; Zhu, Xiaojun; Xiong, Jing-Wei

    2013-03-15

    Abnormal cardiac valve morphogenesis is a common cause of human congenital heart disease. The molecular mechanisms regulating endocardial cell proliferation and differentiation into cardiac valves remain largely unknown, although great progress has been made on the endocardial contribution to the atrioventricular cushion and valve formation. We found that scotch tape(te382) (sco(te382)) encodes a novel transmembrane protein that is crucial for endocardial cell proliferation and heart valve development. The zebrafish sco(te382) mutant showed diminished endocardial cell proliferation, lack of heart valve leaflets and abnormal common cardinal and caudal veins. Positional cloning revealed a C946T nonsense mutation of a novel gene pku300 in the sco(te382) locus, which encoded a 540-amino-acid protein on cell membranes with one putative transmembrane domain and three IgG domains. A known G3935T missense mutation of fbn2b was also found ∼570 kb away from pku300 in sco(te382) mutants. The genetic mutant sco(pku300), derived from sco(te382), only had the C946T mutation of pku300 and showed reduced numbers of atrial endocardial cells and an abnormal common cardinal vein. Morpholino knockdown of fbn2b led to fewer atrial endocardial cells and an abnormal caudal vein. Knockdown of both pku300 and fbn2b phenocopied these phenotypes in sco(te382) genetic mutants. pku300 transgenic expression in endocardial and endothelial cells, but not myocardial cells, partially rescued the atrial endocardial defects in sco(te382) mutants. Mechanistically, pku300 and fbn2b were required for endocardial cell proliferation, endocardial Notch signaling and the proper formation of endocardial cell adhesion and tight junctions, all of which are crucial for cardiac valve development. We conclude that pku300 and fbn2b represent the few genes capable of regulating endocardial cell proliferation and signaling in zebrafish cardiac valve development.

  12. Management of Newborn Infants with Phenylketonuria.

    ERIC Educational Resources Information Center

    Health Services Administration (DHEW/PHS), Rockville, MD. Bureau of Community Health Services.

    The booklet covers the identification, diagnosis, and clinical treatment of newborns with Phenylketonuria (PKU), an inborn error of metabolism, which, if untreated, can lead to mental retardation. An initial section considers biochemical and genetic factors of PKU including a diagram of aromatic amino acid hydroxylation systems. Screening…

  13. Management of Newborn Infants with Phenylketonuria.

    ERIC Educational Resources Information Center

    Health Services Administration (DHEW/PHS), Rockville, MD. Bureau of Community Health Services.

    The booklet covers the identification, diagnosis, and clinical treatment of newborns with Phenylketonuria (PKU), an inborn error of metabolism, which, if untreated, can lead to mental retardation. An initial section considers biochemical and genetic factors of PKU including a diagram of aromatic amino acid hydroxylation systems. Screening…

  14. Molecular genetics and diagnosis of phenylketonuria: state of the art.

    PubMed

    Blau, Nenad; Shen, Nan; Carducci, Carla

    2014-07-01

    Detection of individuals with phenylketonuria (PKU), an autosomal recessively inherited disorder in phenylalanine degradation, is straightforward and efficient due to newborn screening programs. A recent introduction of the pharmacological treatment option emerged rapid development of molecular testing. However, variants responsible for PKU do not all suppress enzyme activity to the same extent. A spectrum of over 850 variants, gives rise to a continuum of hyperphenylalaninemia from very mild, requiring no intervention, to severe classical PKU, requiring urgent intervention. Locus-specific and genotypes database are today an invaluable resource of information for more efficient classification and management of patients. The high-tech molecular methods allow patients' genotype to be obtained in a few days, especially if each laboratory develops a panel for the most frequent variants in the corresponding population.

  15. Adult phenylketonuria presenting with subacute severe neurologic symptoms.

    PubMed

    Seki, M; Takizawa, T; Suzuki, S; Shimizu, T; Shibata, H; Ishii, T; Hasegawa, T; Suzuki, N

    2015-08-01

    We report a 48-year-old Japanese woman with phenylketonuria (PKU) who presented with severe neurological symptoms more than 30 years after discontinuation of dietary treatment. She was diagnosed with PKU at 6-years-old and was treated with a phenylalanine restricted diet until she was 15 years old. When she was 48-years-old she started having difficulty walking. After several months, she presented with severe disturbance of consciousness and was admitted. She was diagnosed as having neurological complications associated with PKU. We observed temporal changes in her laboratory data, brain MRI and single-photon emission computed tomography (SPECT) scan findings. Brain MRI on T2-weighted, fluid-attenuated inversion recovery and diffusion-weighted images revealed high intensity lesions in her bilateral frontal lobes and 123I-IMP SPECT showed marked and diffuse hypoperfusion in the bilateral cerebrum and cerebellum. After the resumption of dietary treatment, serum phenylalanine concentrations immediately decreased to the normal range. However, her neurological symptoms took longer to improve. We also found no clear temporal association between MRI findings and clinical severity. SPECT abnormalities showed marked improvement after treatment. It is well known that PKU patients who discontinue the dietary restriction from their childhood develop minor neurological impairments. However, PKU patients with late-onset severe neurological symptoms are very rare. To our knowledge, this is the first report regarding SPECT findings of PKU patients with late-onset severe neurological deterioration. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Breastfeeding Infants with Phenylketonuria in the United States and Canada

    PubMed Central

    Press, Nancy; Knafl, Kathleen A.; Steiner, Robert D.; Houck, Gail M.

    2014-01-01

    Abstract Objective: This study described the prevalence and duration of mothers' breastfeeding infants with phenylketonuria (PKU) and explored factors related to duration of breastfeeding as a surrogate for breastfeeding success. Subjects and Methods: Descriptive analysis as performed from an international Internet survey of mothers (n=103) who met the inclusion criteria: (1) at least 21 years of age, (2) able to read and write in English, (3) child with PKU, and (4) living in the United States or Canada. Results: Of the 103 mothers, 89 (86%) initiated breastfeeding immediately following delivery, whereas 14 (14%) chose bottle feeding. In comparison to breastfeeding after delivery, significantly fewer mothers breastfed after diagnosis (McNemar's χ2=30.33, p<0.001; n=72 vs. n=89). Breastfeeding duration ranged from less than 1 month to 24 months with one modal duration category (n=20, 22%) at less than 1 month. The timing of the addition of commercial infant formula to supplement breastfeeding or expressed mothers' milk was associated with a shorter duration of breastfeeding among infants with PKU: χ2 (42, n=73)=88.13, p<0.001. Conclusions: PKU is treated with phenylalanine (Phe) restriction. Breastfeeding infants with PKU is challenging in part because Phe intake is difficult to determine precisely. We studied breastfeeding duration in infants with PKU and factors associated with success. Further research should identify the unique needs of mothers' breastfeeding infants with PKU to guide the development of interventions specific to these mothers to support their efforts to continue breastfeeding after the diagnosis of PKU. PMID:24350704

  17. PHENYLKETONURIA, A COMPREHENSIVE BIBLIOGRAPHY, 1964.

    ERIC Educational Resources Information Center

    Children's Bureau (DHEW), Washington, DC.

    INTENDED AS AN AID TO PROFESSIONAL AND TECHNICAL PERSONS INTERESTED IN PHENYLKETONURIA (PKU), THE BIBLIOGRAPHY LISTS AND ANNOTATES 817 ITEMS. CONTENT DIVISIONS ARE (1) GENERAL--MONOGRAPHS AND ARTICLES, (2) BIOCHEMISTRY--METABOLISM, EXPERIMENTS, TESTS, AND CASES IN WHICH THE EMPHASIS IS ON BIOCHEMISTRY, (3) GENETICS--GENE STUDIES, HEREDITARY…

  18. PHENYLKETONURIA, A COMPREHENSIVE BIBLIOGRAPHY, 1964.

    ERIC Educational Resources Information Center

    Children's Bureau (DHEW), Washington, DC.

    INTENDED AS AN AID TO PROFESSIONAL AND TECHNICAL PERSONS INTERESTED IN PHENYLKETONURIA (PKU), THE BIBLIOGRAPHY LISTS AND ANNOTATES 817 ITEMS. CONTENT DIVISIONS ARE (1) GENERAL--MONOGRAPHS AND ARTICLES, (2) BIOCHEMISTRY--METABOLISM, EXPERIMENTS, TESTS, AND CASES IN WHICH THE EMPHASIS IS ON BIOCHEMISTRY, (3) GENETICS--GENE STUDIES, HEREDITARY…

  19. Challenges to breastfeeding infants with phenylketonuria.

    PubMed

    Banta-Wright, Sandra A; Kodadek, Sheila M; Steiner, Robert D; Houck, Gail M

    2015-01-01

    Breastfeeding duration for infants with phenylketonuria (PKU) is less than other full-term infants. However, no study has examined the challenges encountered by mothers' breastfeeding infants with PKU. In 75 mothers of a child with PKU, three categories of breastfeeding challenges were identified: common breastfeeding issues, breastfeeding and PKU, and no challenges. The common breastfeeding issues can be identified in the literature but for these mothers, the issues are heightened due to frequent phenylalanine (Phe) monitoring. Even so, many mothers adapt breastfeeding to maintain desired Phe levels. A few mothers had no issues and were the exception, not the norm.

  20. Surface-enhanced Raman scattering (SERS) for detection of phenylketonuria for newborn screening

    NASA Astrophysics Data System (ADS)

    Javanmard, M.; Davis, R. W.

    2014-02-01

    Diagnosis of Phenylketonuria (PKU) in newborns is important because it can potentially help prevent mental retardation since it is treatable by dietary means. PKU results in phenylketonurics having phenylalanine levels as high as 2 mM whereas the normal upper limit in healthy newborns is 120 uM. To this end, we are developing a microfluidic platform integrated with a SERS substrate for detection of high levels of phenylalanine. We have successfully demonstrated SERS detection of phenylalanine using various SERS substrates fabricated using nanosphere lithography, which exhibit high levels of field enhancement. We show detection of SERS at clinically relevant levels.

  1. Causes of delay in referral of patients with phenylketonuria to a specialized reference centre in Mexico.

    PubMed

    Vela-Amieva, M; Ibarra-González, I; Fernández-Lainez, C; Monroy-Santoyo, S; Guillén-López, S; Belmont-Martínez, L; Hernández-Montiel, A

    2011-01-01

    To expose causes leading to the delayed arrival of phenylketonuria (PKU) patients at a governmental reference centre (RC), and to describe their clinical characteristics. Material and methods PKU files registered during the past 18 years at the National Institute of Pediatrics in Mexico City were evaluated. Patients were classified into two groups according to their age at arrival: Group I (early reference), patients arriving during the first month of life; and Group II (late reference), those who arrived after thirty days of age. Time and causes of delay were documented. Of 57 recorded files, 10 were classified in Group I and 47 in Group II. Causes leading to the late arrival of Group II patients were absence of routine newborn screening (NBS), PKU not included in the routine NBS, sampling after the recommended age, false negative result, results without interpretation and/or instructions to follow, delayed notification of results, poor medical criteria of attending physician, difficulties in obtaining confirmatory tests, and administrative failures. The main cause of late referral of PKU patients was the absence of PKU testing. As a developing country, Mexico still faces challenges in the proper functioning and expansion of the NBS programme. Most PKU patients arrived at the RC late, presenting with varying degrees of the clinical spectrum. Incorporating PKU testing into the already established Mexican NBS system and adding quality indicators to guarantee proper operation in all NBS phases is necessary to achieve the goal of identifying, referring, diagnosing, and treating patients promptly.

  2. [The maternal phenylketonuria syndrom--still current problem].

    PubMed

    Didycz, Bozena; Domagała, Lucyna; Pietrzyk, Jacek J

    2009-01-01

    Phenylketonuria (OMIM 261600) is a congenital genetically conditioned error of metabolism phenylalanine to tyrosine. Being untreated or insufficiently treated phenylketonuria (PKU) sometimes leads to irreversible damage of mielin. Similarly, high phenylalanine concentration in the blood of pregnant woman with PKU exert the teratogenic effect on growing and developing foetus (in the majority of cases being the carrier of PKU), which leads to appearance of maternal phenylketonuria syndrom (MPKU syndrom). The features of MPKU syndrome consist: low weight at birth, the congenital heart defects, digestive tract defects, osseous arrangements, microcephaly, handicap of intellectual development. Spontaneous miscarriages at pregnant women with PKU are more often. the evaluation of influence hyperphenylalaninemia of pregnant woman with PKU on her foetus, depending on the metabolic control in the pre- and postconception period. under the care of Outpatient Metabolic Clinic of University Children's Hospital in Cracow remain 430 patients aged from 0 to 56 years with hyperphenylalaninemia. In the register of Outpatient Metabolic Clinic there are the data about 50 pregnancies of 21 women with hyperphylalaninemia (from mild hyperphenylalaninemia to classic PKU). Only 10 pregnancies were planned - the low-phenylalanine diet was obligatory introduced 3 months before conception and was applied throughout the whole period of pregnancy in order to maintain the levels of phenylalanine in the range of 2 to 6 mg/dl. One pregnancy finished with spontaneous miscarriage, the other 9- the birth of healthy offspring. By contrast, out of 40 unplanned pregnancies 8 ended in spontaneous miscarriage, and of the remaining 32 unplanned pregnancies 33 children were born: 24 (75%) newborns with the maternal PKU features, 1 child died during thel-st year of life, 3 have the lack of any data, and only 5 (15.6%) children were born clinically healthy (1 twin birth). Among the children with maternal PKU

  3. Purification and Use of Glycomacropeptide for Nutritional Management of Phenylketonuria

    PubMed Central

    LaClair, Caitlin E.; Ney, Denise M.; MacLeod, Erin L.; Etzel, Mark R.

    2013-01-01

    Individuals with phenylketonuria (PKU) cannot metabolize phenylalanine (Phe) and must adhere to a low-Phe diet in which most dietary protein is provided by a Phe-free amino acid formula. Glycomacropeptide (GMP) is the only naturally occurring protein that does not contain Phe, and is of interest as a source of protein for dietary management of PKU. However, commercially available GMP contains too much Phe from residual whey proteins and does not contain adequate levels of all the indispensable amino acids to provide a nutritionally complete protein. The aim of this study was to increase purity of GMP and develop a mass balance calculation for indispensable amino acid supplementation of GMP foods. Cation exchange chromatography, ultrafiltration/diafiltration, and lyophilization were used at the pilot plant scale to decrease Phe. Enough purified GMP (5 kg) was manufactured to provide 15 PKU subjects with a 4-d diet in which the majority of protein was from GMP foods. A mass balance was used to supplement GMP foods so that all indispensable amino acids met or exceeded the daily recommended intake. GMP foods were tested in a human clinical trial as a replacement for the traditional amino acid formula. Nutritionally complete GMP foods created with high purity GMP provide individuals with PKU with more options to manage PKU, which may lead to improved compliance and quality of life. PMID:19490325

  4. PKU and the Schools: Information for Teachers, Administrators and Other School Personnel.

    ERIC Educational Resources Information Center

    Health Services Administration (DHEW/PHS), Rockville, MD. Bureau of Community Health Services.

    Designed to acquaint teachers, administrators and other school personnel with phenylketonuria (PKU - an inborn error of metabolism which requires dietary intervention), the booklet reviews school problems related to the condition. Introductory information concerns the nature, treatment, and screening and diagnosis of PKU. Diet management is…

  5. PKU and the Schools: Information for Teachers, Administrators and Other School Personnel.

    ERIC Educational Resources Information Center

    Health Services Administration (DHEW/PHS), Rockville, MD. Bureau of Community Health Services.

    Designed to acquaint teachers, administrators and other school personnel with phenylketonuria (PKU - an inborn error of metabolism which requires dietary intervention), the booklet reviews school problems related to the condition. Introductory information concerns the nature, treatment, and screening and diagnosis of PKU. Diet management is…

  6. Long-term changes in glutamatergic synaptic transmission in phenylketonuria.

    PubMed

    Glushakov, A V; Glushakova, O; Varshney, M; Bajpai, L K; Sumners, C; Laipis, P J; Embury, J E; Baker, S P; Otero, D H; Dennis, D M; Seubert, C N; Martynyuk, A E

    2005-02-01

    The cellular mechanisms that underlie impaired brain function during phenylketonuria (PKU), the most common biochemical cause of mental retardation in humans, remain unclear. Acute application of L-Phe at concentrations observed in the PKU brain depresses glutamatergic synaptic transmission but does not affect GABA receptor activity in cultured neurons. If these depressant effects of L-Phe take place in the PKU brain, then chronic impairment of the glutamate system, which may contribute to impaired brain function, could be detected as changes in postsynaptic glutamate receptors. This hypothesis was tested by using a combination of liquid chromatography-mass spectrometry, patch-clamp, radioligand binding and western blot approaches in forebrain tissue from heterozygous and homozygous (PKU) Pah(enu2) mice. Brain concentrations of L-Phe were nearly six-fold greater in PKU mice (863.12 +/- 17.96 micromol/kg) than in their heterozygous counterparts (149.32 +/- 10.23 micromol/kg). This concentration is significantly higher than the K(B) of 573 microM for L-Phe to compete for N-methyl-D-aspartate (NMDA) receptors. Receptor binding experiments with [3H]MK-801 showed significant up-regulation of NMDA receptor density in PKU mice. Consistent with the depressant effects of L-Phe, expression of NMDA receptor NR2A and (RS)-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor Glu1 and Glu2/3 subunits was significantly increased, whereas expression of the NR2B subunit was decreased. There was no change in GABA alpha1 subunit expression. Given the role of the glutamatergic system in brain development and function, these changes may, at least in part, explain the brain disorders associated with PKU.

  7. Descriptive and hedonic analyses of low-Phe food formulations containing corn (Zea mays) seedling roots: toward development of a dietary supplement for individuals with phenylketonuria.

    PubMed

    Cliff, Margaret A; Law, Jessica R; Lücker, Joost; Scaman, Christine H; Kermode, Allison R

    2016-01-15

    Seedling roots of anthocyanin-rich corn (Zea mays) cultivars contain high levels of phenylalanine ammonia lyase (PAL) activity. The development of a natural dietary supplement containing corn roots could provide the means to improve the restrictive diet of phenylketonuria (PKU) patients by increasing their tolerance to dietary phenylalanine (Phe). Therefore this research was undertaken to explore the sensory characteristics of roots of four corn cultivars as well as to develop and evaluate food products (cereal bar, beverage, jam-like spread) to which roots had been added. Sensory profiles of corn roots were investigated using ten trained judges. Roots of Japanese Striped corn seedlings were more bitter, pungent and astringent than those of white and yellow cultivars, while roots from the Blue Jade cultivar had a more pronounced earthy/mushroom aroma. Consumer research using 24 untrained panelists provided hedonic (degree-of-liking) assessments for products with and without roots (controls). The former had lower mean scores than the controls; however, the cereal bar had scores above 5 on the nine-point scale for all hedonic assessments compared with the other treated products. By evaluating low-Phe food products containing corn roots, this research ascertained that the root-containing low-Phe cereal bar was an acceptable 'natural' dietary supplement for PKU-affected individuals. © 2015 Her Majesty the Queen in Right of Canada. Journal of the Science of Food and Agriculture © 2015 Society of Chemical Industry.

  8. Caring for children with phenylketonuria

    PubMed Central

    Casey, Linda

    2013-01-01

    Abstract Objective To provide an overview of the diagnosis and management of phenylketonuria (PKU) in childhood with an emphasis on aspects relevant to family physicians providing ongoing care. Sources of information The author’s experience as the clinic physician in a regional pediatric PKU clinic is supplemented with references providing evidence for key points. Main message While metabolic clinics typically provide guidance regarding the specific management of PKU, the family doctor has an essential role in providing ongoing medical care. Conclusion Children and families have much to gain from strong relationships with family doctors, and family doctors can confidently provide care with awareness of the very few potential special needs of patients with PKU. PMID:23946023

  9. Mouse Models of Human Phenylketonuria

    PubMed Central

    Shedlovsky, A.; McDonald, J. D.; Symula, D.; Dove, W. F.

    1993-01-01

    Phenylketonuria (PKU) results from a deficiency in phenylalanine hydroxylase, the enzyme catalyzing the conversion of phenylalanine (PHE) to tyrosine. Although this inborn error of metabolism was among the first in humans to be understood biochemically and genetically, little is known of the mechanism(s) involved in the pathology of PKU. We have combined mouse germline mutagenesis with screens for hyperphenylalaninemia to isolate three mutants deficient in phenylalanine hydroxylase (PAH) activity and cross-reactive protein. Two of these have reduced PAH mRNA and display characteristics of untreated human PKU patients. A low PHE diet partially reverses these abnormalities. Our success in using high frequency random germline point mutagenesis to obtain appropriate disease models illustrates how such mutagenesis can complement the emergent power of targeted mutagenesis in the mouse. The mutants now can be used as models in studying both maternal PKU and somatic gene therapy. PMID:8375656

  10. Late-Treated Phenylketonuria and Partial Reversibility of Intellectual Impairment

    ERIC Educational Resources Information Center

    Grosse, Scott D.

    2010-01-01

    Individuals with late-treated phenylketonuria (PKU) not detected by newborn screening but who followed dietary treatment for at least 12 months before 7 years of age have intelligence quotient (IQ) scores that range from severe impairment to the low-normal range. Among adults with late-treated PKU in California, 85% of those who were born from…

  11. Transitory Hyperphenylalaninaemia in Children with Continuously Treated Phenylketonuria.

    ERIC Educational Resources Information Center

    Griffiths, Peter; Smith, Caroline; Harvie, Ann

    1997-01-01

    Cognitive and behavioral effects of temporarily elevating levels of phenylalanine in treated phenylketonuria (PKU) were investigated in a triple-blind crossover study with 16 early and continuously treated children and adolescents with PKU. Results suggest that intellectual ability, memory, and conduct are not affected by medium-term elevated…

  12. Late-Treated Phenylketonuria and Partial Reversibility of Intellectual Impairment

    ERIC Educational Resources Information Center

    Grosse, Scott D.

    2010-01-01

    Individuals with late-treated phenylketonuria (PKU) not detected by newborn screening but who followed dietary treatment for at least 12 months before 7 years of age have intelligence quotient (IQ) scores that range from severe impairment to the low-normal range. Among adults with late-treated PKU in California, 85% of those who were born from…

  13. Transitory Hyperphenylalaninaemia in Children with Continuously Treated Phenylketonuria.

    ERIC Educational Resources Information Center

    Griffiths, Peter; Smith, Caroline; Harvie, Ann

    1997-01-01

    Cognitive and behavioral effects of temporarily elevating levels of phenylalanine in treated phenylketonuria (PKU) were investigated in a triple-blind crossover study with 16 early and continuously treated children and adolescents with PKU. Results suggest that intellectual ability, memory, and conduct are not affected by medium-term elevated…

  14. Food acceptance and neophobia in children with phenylketonuria: a prospective controlled study.

    PubMed

    Evans, S; Daly, A; Chahal, S; MacDonald, J; MacDonald, A

    2016-08-01

    In phenylketonuria (PKU), little is known about the effect of bitter-tasting phenylalanine-free l-amino acid exposure on taste preference development. The present prospective study aimed to determine the flavour preferences of children with PKU versus healthy control children. Thirty-five children with PKU and 35 age/gender-matched controls, aged 4-13 years, tasted 10 blinded puree foods in random order. They were rated using a seven-point pictorial hedonic scale (super yummy to super yucky) and ranked in preferential order. Caregivers completed a neophobia and food frequency questionnaire on behalf of their children. Both PKU and control groups rated sweet foods higher than savoury, bitter and sour foods. However, control children ranked fruits as a group higher than PKU children (mean 3.7 versus 4.6; P = 0.03), whereas PKU children ranked vegetables as a group higher than controls (mean 5.6 versus 6.3; P = 0.05). Children with PKU had more neophobia and were untrusting/fearful of new foods. Although there was some evidence to suggest that children with PKU aged ≥4 years prefer savoury foods (vegetables) more than control children, they did not prefer bitter-tasting foods, and so early and persistent administration of bitter-tasting l-amino acids was not associated with apparent taste imprinting. Neophobia appears to play significant part in food refusal in PKU, perhaps more so than taste preferences. © 2015 The British Dietetic Association Ltd.

  15. Updated, web-based nutrition management guideline for PKU: An evidence and consensus based approach.

    PubMed

    Singh, Rani H; Cunningham, Amy C; Mofidi, Shideh; Douglas, Teresa D; Frazier, Dianne M; Hook, Debra Geary; Jeffers, Laura; McCune, Helen; Moseley, Kathryn D; Ogata, Beth; Pendyal, Surekha; Skrabal, Jill; Splett, Patricia L; Stembridge, Adrya; Wessel, Ann; Rohr, Frances

    2016-06-01

    In 2014, recommendations for the nutrition management of phenylalanine hydroxylase deficiency were published as a companion to the concurrently published American College of Medical Genetics and Genomics guideline for the medical treatment of phenylketonuria (PKU). These were developed primarily from a summary of findings from the PKU scientific review conference sponsored by the National Institutes of Health and Agency for Healthcare Research & Quality along with additional systematic literature review. Since that time, the Genetic Metabolic Dietitians International and the Southeast Regional Newborn Screening and Genetics Collaborative have partnered to create a web-based technology platform for the update and development of nutrition management guidelines for inherited metabolic disorders. The purpose of this PKU guideline is to establish harmonization in treatment and monitoring, to guide the integration of nutrition therapy in the medical management of PKU, and to improve outcomes (nutritional, cognitive, and developmental) for individuals with PKU in all life stages while reducing associated medical, educational, and social costs. Six research questions critical to PKU nutrition management were formulated to support guideline development: Review, critical appraisal, and abstraction of peer-reviewed studies and unpublished practice literature, along with expert Delphi survey feedback, nominal group process, and external review from metabolic physicians and dietitians were utilized for development of recommendations relevant to each question. Recommendations address nutrient intake, including updated protein requirements, optimal blood phenylalanine concentrations, nutrition interventions, monitoring parameters specific to life stages, adjunct therapies, and pregnancy and lactation. Recommendations were graded using a rigorous system derived from the Academy of Nutrition and Dietetics. These guidelines, updated utilizing a thorough and systematic approach to

  16. Diet Management of PKU for Infants and Preschool Children.

    ERIC Educational Resources Information Center

    Acosta, Phyllis B.; Wenz, Elizabeth

    The report focuses on the diet management of infant and preschool children with phenylketonuria (PKU), a congenital deficiency resulting in brain damage. The effective methods for rapidly lowering serum phenylalanine levels following diagnosis are discussed, a method for prescribing and calculating the phenylalanine-restricted diet is described,…

  17. A GC/MS-based metabolomic approach for reliable diagnosis of phenylketonuria.

    PubMed

    Xiong, Xiyue; Sheng, Xiaoqi; Liu, Dan; Zeng, Ting; Peng, Ying; Wang, Yichao

    2015-11-01

    Although the phenylalanine/tyrosine ratio in blood has been the gold standard for diagnosis of phenylketonuria (PKU), the disadvantages of invasive sample collection and false positive error limited the application of this discriminator in the diagnosis of PKU to some extent. The aim of this study was to develop a new standard with high sensitivity and specificity in a less invasive manner for diagnosing PKU. In this study, an improved oximation-silylation method together with GC/MS was utilized to obtain the urinary metabolomic information in 47 PKU patients compared with 47 non-PKU controls. Compared with conventional oximation-silylation methods, the present approach possesses the advantages of shorter reaction time and higher reaction efficiency at a considerably lower temperature, which is beneficial to the derivatization of some thermally unstable compounds, such as phenylpyruvic acid. Ninety-seven peaks in the chromatograms were identified as endogenous metabolites by the National Institute of Standards and Technology (NIST) mass spectra library, including amino acids, organic acids, carbohydrates, amides, and fatty acids. After normalization of data using creatinine as internal standard, 19 differentially expressed compounds with p values of <0.05 were selected by independent-sample t test for the separation of the PKU group and the control group. A principal component analysis (PCA) model constructed by these differentially expressed compounds showed that the PKU group can be discriminated from the control group. Receiver-operating characteristic (ROC) analysis with area under the curve (AUC), specificity, and sensitivity of each PKU marker obtained from these differentially expressed compounds was used to evaluate the possibility of using these markers for diagnosing PKU. The largest value of AUC (0.987) with high specificity (0.936) and sensitivity (1.000) was obtained by the ROC curve of phenylacetic acid at its cutoff value (17.244 mmol/mol creatinine

  18. Fifty years of phenylketonuria newborn screening - A great success for many, but what about the rest?

    PubMed

    Groselj, Urh; Tansek, Mojca Zerjav; Battelino, Tadej

    2014-01-01

    Guthrie's landmark discovery and the subsequent implementation of the first newborn screening programs for phenylketonuria (PKU) and other inherited errors of metabolism (IEM) could be - in a 50 year retrospective - easily considered among the greatest advances in medicine. They have not just improved the quality of hundreds of thousands of lives, but also transformed our understanding and approach to PKU and IEM in general. However, according to the available albeit very scarce data, many countries and regions seem not to share the benefits of the last 50 years of development. Many of them have not yet introduced the newborn screening for PKU or face significant problems in its implementation. In addition, the issue seems to be underrated by the relevant professional forums. Action to improve the current situation should urgently be taken. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Anthropological significance of phenylketonuria.

    PubMed

    Saugstad, L F

    1975-01-01

    The highest incidence rates of phenylketonuria (PKU) have been observed in Ireland and Scotlant. Parents heterozygous for PKU in Norway differ significantly from the general population in the Rhesus, Kell and PGM systems. The parents investigated showed an excess of Rh negative, Kell plus and PGM type 1 individuals, which makes them similar to the present populations in Ireland and Scotlant. It is postulated that the heterozygotes for PKU in Norway are descended from a completely assimilated sub-population of Celtic origin, who came or were brought here, 1ooo years ago. Bronze objects of Western European (Scottish, Irish) origin, found in Viking graves widely distributed in Norway, have been taken as evidence of Vikings returning with loot (including a number of Celts) from Western Viking settlements. The continuity of residence since the Viking age in most habitable parts of Norway, and what seems to be a nearly complete regional relationship between the sites where Viking graves contain western imported objects and the birthplaces of grandparents of PKUs identified in Norway, lend further support to the hypothesis that the heterozygotes for PKU in Norway are descended from a completely assimilated subpopulation. The remarkable resemblance between Iceland and Ireland, in respect of several genetic markers (including the Rhesus, PGM and Kell systems), is considered to be an expression of a similar proportion of people of Celtic origin in each of the two countries. Their identical, high incidence rates of PKU are regarded as further evidence of this. The significant decline in the incidence of PKU when one passes from Ireland, Scotland and Iceland, to Denmark and on to Norway and Sweden, is therefore explained as being related to a reduction in the proportion of inhabitants of Celtic extraction in the respective populations.

  20. PKU Self-Management Timeline

    MedlinePlus

    ... pku UW PKU Clinic News & Events PKU Self-Management Timeline This timeline is also available as an ... file. Click here to download. The PKU Self- Management timeline is included to provide long-term view ...

  1. Intellectual, neurologic, and neuropsychologic outcome in untreated subjects with nonphenylketonuria hyperphenylalaninemia. German Collaborative Study on Phenylketonuria.

    PubMed

    Weglage, J; Ullrich, K; Pietsch, M; Fünders, B; Güttler, F; Harms, E

    1997-09-01

    Based on the serum phenylalanine levels under free diet patients with hyperphenylalaninemia are classified as "classical" (>1200 micromol/L), "mild" (600-1200 micromol/L), or "non-phenylketonuria (PKU)-hyperphenylalaninemia" (<600 micromol/L). Recent studies revealed intellectual, neurologic, and neuropsychologic deficits as well as abnormalities of cerebral white matter (magnetic resonance imaging, MRI) in patients with early and adequately treated PKU. In addition deficits in IQ were reported for a group of 4-y-old patients with untreated mild PKU and non-PKU hyperphenylalaninemia (serum phenylalanine levels below 900 micromol/L). As a consequence, a lifelong diet with serum phenylalanine levels below 400 micromol/L was recommended even for those patients with serum phenylalanine levels remaining consistently between 400 and 600 micromol/L. Generally patients with non-PKU hyperphenylalaninemia were not treated, as a normal outcome was suspected, but the clinical development of patients with non-PKU hyperphenylalaninemia was not so far studied systematically. We assessed 28 untreated patients with non-PKU hyperphenylalaninemia (age: mean = 21.8, SD = 4.2 y) for IQ, school and job career, clinical-neurologic development, fine motor performances, selective and sustained attention, as well as for frontal lobe-dependent "executive functions." In addition, cranial MRI was obtained in 10 of these patients. Compared with healthy control subjects, matched for age, sex, and socioeconomic status, the patients reached normal results in all clinical and psychometric tests. Cranial MRI revealed no abnormalities. Additionally, no significant correlations between serum phenylalanine levels and test results were obtained. In the absence of any demonstrative effect, treatment is unlikely to be of significant effect in patients with non-PKU hyperphenylalaninemia.

  2. National PKU News

    MedlinePlus

    ... and History Staff & Board How Much Phe Guthrie-Koch Scholarship Books Resources Support Us Contact Us Donors ... new Amino Acid Analysis Results This Year’s Guthrie-Koch PKU Scholarship Winners © 2016 National PKU News

  3. Altered DNA methylation in PAH deficient phenylketonuria.

    PubMed

    Dobrowolski, Steven F; Lyons-Weiler, James; Spridik, Kayla; Biery, Amy; Breck, Jane; Vockley, Jerry; Yatsenko, Svetlana; Sultana, Tamanna

    2015-01-01

    While phenylalanine (PHE) is the toxic insult in phenylketonuria (PKU), mechanisms underlying PHE toxicity remain ill-defined. Altered DNA methylation in response to toxic exposures is well-recognized. DNA methylation patterns were assessed in blood and brain from PKU patients to determine if PHE toxicity impacts methylation. Methylome assessment, utilizing methylated DNA immunoprecipitation and paired-end sequencing, was performed in DNA obtained from brain tissue of classical PKU patients, leukocytes from poorly controlled PKU patients, leukocytes from well controlled PKU patients, and appropriate control tissues. In PKU brain tissue, expression analysis determined the impact of methylation on gene function. Differential methylation was observed in brain tissue of PKU patients and expression studies identified downstream impact on gene expression. Altered patterns of methylation were observed in leukocytes of well controlled and poorly controlled patients with more extensive methylation in patients with high PHE exposure. Differential methylation of noncoding RNA genes was extensive in patients with high PHE exposure but minimal in well controlled patients. Methylome repatterning leading to altered gene expression was present in brain tissue of PKU patients, suggesting a role in neuropathology. Aberrant methylation is observed in leukocytes of PKU patients and is influenced by PHE exposure. DNA methylation may provide a biomarker relating to historic PHE exposure. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Intelligence and Phenylketonuria: Effects of Diet Termination.

    ERIC Educational Resources Information Center

    Koff, Elissa; And Others

    1979-01-01

    Trends in intellectual functioning before and after diet termination were examined in 30 children (5-11 years old) with PKU (Phenylketonuria, a metabolic disorder) treated before 6 weeks of age and on a liberal diet for a mean of 3 years since the mean age of 59 months. Journal availability: C.V. Mosby Company, 11830 Westline Industrial Drive, St.…

  5. Early-Treated Phenylketonuria: Neuropsychologic Consequences.

    ERIC Educational Resources Information Center

    Brunner, Robert L.; And Others

    1983-01-01

    The neuropsychologic performance of 27 children (about 6 to 13 years old) with early-treated phenylketonuria (PKU) was evaluated and correlated with their serum phenylalanine concentrations at several ages. (Author/SEW) Journal Availability: The Journal of Pediatrics; The C. V. Mosby Company, 11830 Westline Industrial Drive, St. Louis, MO 63141.

  6. Early-Treated Phenylketonuria: Neuropsychologic Consequences.

    ERIC Educational Resources Information Center

    Brunner, Robert L.; And Others

    1983-01-01

    The neuropsychologic performance of 27 children (about 6 to 13 years old) with early-treated phenylketonuria (PKU) was evaluated and correlated with their serum phenylalanine concentrations at several ages. (Author/SEW) Journal Availability: The Journal of Pediatrics; The C. V. Mosby Company, 11830 Westline Industrial Drive, St. Louis, MO 63141.

  7. Intelligence and Phenylketonuria: Effects of Diet Termination.

    ERIC Educational Resources Information Center

    Koff, Elissa; And Others

    1979-01-01

    Trends in intellectual functioning before and after diet termination were examined in 30 children (5-11 years old) with PKU (Phenylketonuria, a metabolic disorder) treated before 6 weeks of age and on a liberal diet for a mean of 3 years since the mean age of 59 months. Journal availability: C.V. Mosby Company, 11830 Westline Industrial Drive, St.…

  8. Delayed diagnosis of phenylketonuria - a case report of two siblings.

    PubMed

    Narayanan, Deepa; Barski, Robert; Henderson, Mick J; Luvai, Ahai; Chandrajay, Deepak; Stainforth, Collette; Bradley, Jacqueline; Rogozinski, Hazel; Sharma, Reena

    2014-05-01

    Phenylketonuria (PKU), is an autosomal recessive condition affecting the amino acid metabolism. The UK National newborn screening programme was commenced in 1969 and PKU is one among the five conditions included in the screening programme. We present the case history of two siblings of a family with a delayed diagnosis of PKU. This case history highlights such an occurrence. PKU should be considered as an important differential in the diagnosis of adult patients with learning difficulties, seizures and behavioural problems. It would be prudent to instigate plasma and urine amino/organic acid analyses in adult patients with unexplained neuropsychological manifestations.

  9. Central precocious puberty in a 3 year-old girl with Phenylketonuria: a rare association?

    PubMed Central

    2014-01-01

    Background Central precocious puberty (CPP) and phenylketonuria (PKU) are two rare conditions, the latter being the rarer. To date, only one case featuring both these conditions has been reported, and hyperphenylalaninemia was assumed triggering CPP. Case presentation We present a 3.2 years old girl referred with a 12 months history of breast and pubic hair development, and vaginal discharge. Hyperphenylalaninemia had been identified by newborn screening and PKU subsequently confirmed by plasma amino acid and genetic analysis. Early dietary control of plasma phenylalanine had been excellent afterwards, resulting in phenylalanine concentrations consistently within the recommended range. Clinical scenario, hormonal assessment and imaging were in keeping with true idiopathic central precocious puberty. Treatment with long lasting gonadotropin-releasing hormone analogue led to regression of secondary sexual characteristics. Conclusion We describe for the first time CPP in a girl affected with PKU but with persistently well controlled blood phenylalanine concentrations. This finding is in contrast to a previous report which suggested persistently high phenylalaninemia levels as potential trigger for CPP in PKU patients. Our report, together with the lack of evidence in published cohort studies of children with PKU, strongly suggests this rare association is coincidental and independent of the presence of severe hyperphenylalaninemia. PMID:24773629

  10. Phenylketonuria Scientific Review Conference: state of the science and future research needs.

    PubMed

    Camp, Kathryn M; Parisi, Melissa A; Acosta, Phyllis B; Berry, Gerard T; Bilder, Deborah A; Blau, Nenad; Bodamer, Olaf A; Brosco, Jeffrey P; Brown, Christine S; Burlina, Alberto B; Burton, Barbara K; Chang, Christine S; Coates, Paul M; Cunningham, Amy C; Dobrowolski, Steven F; Ferguson, John H; Franklin, Thomas D; Frazier, Dianne M; Grange, Dorothy K; Greene, Carol L; Groft, Stephen C; Harding, Cary O; Howell, R Rodney; Huntington, Kathleen L; Hyatt-Knorr, Henrietta D; Jevaji, Indira P; Levy, Harvey L; Lichter-Konecki, Uta; Lindegren, Mary Lou; Lloyd-Puryear, Michele A; Matalon, Kimberlee; MacDonald, Anita; McPheeters, Melissa L; Mitchell, John J; Mofidi, Shideh; Moseley, Kathryn D; Mueller, Christine M; Mulberg, Andrew E; Nerurkar, Lata S; Ogata, Beth N; Pariser, Anne R; Prasad, Suyash; Pridjian, Gabriella; Rasmussen, Sonja A; Reddy, Uma M; Rohr, Frances J; Singh, Rani H; Sirrs, Sandra M; Stremer, Stephanie E; Tagle, Danilo A; Thompson, Susan M; Urv, Tiina K; Utz, Jeanine R; van Spronsen, Francjan; Vockley, Jerry; Waisbren, Susan E; Weglicki, Linda S; White, Desirée A; Whitley, Chester B; Wilfond, Benjamin S; Yannicelli, Steven; Young, Justin M

    2014-06-01

    New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 μmol/L. The use

  11. The management of breast feeding among infants with phenylketonuria.

    PubMed

    McCabe, L; Ernest, A E; Neifert, M R; Yannicelli, S; Nord, A M; Garry, P J; McCabe, E R

    1989-01-01

    Treatment for phenylketonuria (PKU) involves using low phenylalanine-free or phenylalanine-free formulas and supplementation with sufficient phenylalanine for normal growth and development. Eighteen infants with phenylketonuria who received breast milk as their primary phenylalanine source were compared with ten other infants with PKU who received their phenylalanine primarily from infant formulas. There were no significant differences between breast-fed and formula-fed infants for serum phenylalanine, serum tyrosine, length, weight, head circumference, haematocrit, haemoglobin, serum iron, total iron binding capacity, percentage iron saturation, ferritin, plasma zinc and total calorie intake. Breast-fed infants did show lower mean corpuscular volume at 3 months and 6 months of age. Breast-fed infants had lower phenylalanine intake at 2, 4, 5 and 6 months of age. Breast-fed infants at 1, 2, 3, 4, 5 and 6 months of age had lower protein intake. Breast feeding may be continued in the newly diagnosed phenylketonuric infant without any apparent adverse nutritional consequences.

  12. Classroom Demonstration of a Spot Test for Pbenylpyruvic Acid and Its Relationship to Phenylketonuria

    ERIC Educational Resources Information Center

    Halkides, Christopher J.

    2004-01-01

    Classical phenylketonuria (PKU) is caused by a lack activity in the enzyme phenylalanine hydroxylase, leading to elevated concentrations of phenylalanine in the blood. A simple demonstration and three advanced demonstrations of a spot test for phenylpyruvic acid and its relationship to phenylketonuria are given.

  13. Classroom Demonstration of a Spot Test for Pbenylpyruvic Acid and Its Relationship to Phenylketonuria

    ERIC Educational Resources Information Center

    Halkides, Christopher J.

    2004-01-01

    Classical phenylketonuria (PKU) is caused by a lack activity in the enzyme phenylalanine hydroxylase, leading to elevated concentrations of phenylalanine in the blood. A simple demonstration and three advanced demonstrations of a spot test for phenylpyruvic acid and its relationship to phenylketonuria are given.

  14. What Is the Diet for PKU?

    MedlinePlus

    Skip to main content. PKU Clinic - University of Washington, Seattle Home | Contact Us | Site Map PKU Management For Health Care Providers RECIPES about pku UW PKU Clinic News & Events What is PKU? What is the diet ...

  15. Metabolic syndrome in children and adolescents with phenylketonuria.

    PubMed

    Kanufre, Viviane C; Soares, Rosângelis D L; Alves, Michelle Rosa A; Aguiar, Marcos J B; Starling, Ana Lúcia P; Norton, Rocksane C

    2015-01-01

    This study aimed to identify markers of metabolic syndrome (MS) in patients with phenylketonuria (PKU). This was a cross-sectional study consisting of 58 PKU patients (ages of 4-15 years): 29 patients with excess weight, and 29 with normal weight. The biochemical variables assessed were phenylalanine (phe), total cholesterol, HDL-c, triglycerides, glucose, and basal insulin. The patients had Homeostasis Model Assessment (HOMA) and waist circumference assessed. No inter-group difference was found for phe. Overweight patients had higher levels of triglycerides, basal insulin, and HOMA, but lower concentrations of HDL-cholesterol, when compared to the eutrophic patients. Total cholesterol/HDL-c was significantly higher in the overweight group. A positive correlation between basal insulin level and HOMA with waist circumference was found only in the overweight group. The results of this study suggest that patients with PKU and excess weight are potentially vulnerable to the development of metabolic syndrome. Therefore, it is necessary to conduct clinical and laboratory monitoring, aiming to prevent metabolic changes, as well as excessive weight gain and its consequences, particularly cardiovascular risk. Copyright © 2014 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  16. [Maternal phenylketonuria].

    PubMed

    Bókay, János; Kiss, Erika; Simon, Erika; Szőnyi, László

    2013-05-05

    Elevated maternal phenylalanine levels during pregnancy are teratogenic, and may result in embryo-foetopathy, which could lead to stillbirth, significant psychomotor handicaps and birth defects. This foetal damage is known as maternal phenylketonuria. Women of childbearing age with all forms of phenylketonuria, including mild variants such as hyperphenylalaninaemia, should receive detailed counselling regarding their risks for adverse foetal effects, optimally before contemplating pregnancy. The most assured way to prevent maternal phenylketonuria is to maintain the maternal phenylalanine levels within the optimal range already before conception and throughout the whole pregnancy. Authors review the comprehensive programme for prevention of maternal phenylketonuria at the Metabolic Center of Budapest, they survey the practical approach of the continuous maternal metabolic control and delineate the outcome of pregnancies of mothers with phenylketonuria from the introduction of newborn screening until most recently.

  17. Therapeutic brain modulation with targeted large neutral amino acid supplements in the Pah-enu2 phenylketonuria mouse model.

    PubMed

    van Vliet, Danique; Bruinenberg, Vibeke M; Mazzola, Priscila N; van Faassen, Martijn Hjr; de Blaauw, Pim; Pascucci, Tiziana; Puglisi-Allegra, Stefano; Kema, Ido P; Heiner-Fokkema, M Rebecca; van der Zee, Eddy A; van Spronsen, Francjan J

    2016-11-01

    Phenylketonuria treatment consists mainly of a Phe-restricted diet, which leads to suboptimal neurocognitive and psychosocial outcomes. Supplementation of large neutral amino acids (LNAAs) has been suggested as an alternative dietary treatment strategy to optimize neurocognitive outcome in phenylketonuria and has been shown to influence 3 brain pathobiochemical mechanisms in phenylketonuria, but its optimal composition has not been established. In order to provide additional pathobiochemical insight and develop optimal LNAA treatment, several targeted LNAA supplements were investigated with respect to all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria. Pah-enu2 (PKU) mice received 1 of 5 different LNAA-supplemented diets beginning at postnatal day 45. Control groups included phenylketonuria mice receiving an isonitrogenic and isocaloric high-protein diet or the AIN-93M diet, and wild-type mice receiving the AIN-93M diet. After 6 wk, brain and plasma amino acid profiles and brain monoaminergic neurotransmitter concentrations were measured. Brain Phe concentrations were most effectively reduced by supplementation of LNAAs, such as Leu and Ile, with a strong affinity for the LNAA transporter type 1. Brain non-Phe LNAAs could be restored on supplementation, but unbalanced LNAA supplementation further reduced brain concentrations of those LNAAs that were not (sufficiently) included in the LNAA supplement. To optimally ameliorate brain monoaminergic neurotransmitter concentrations, LNAA supplementation should include Tyr and Trp together with LNAAs that effectively reduce brain Phe concentrations. The requirement for Tyr supplementation is higher than it is for Trp, and the relative effect of brain Phe reduction is higher for serotonin than it is for dopamine and norepinephrine. The study shows that all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria can be targeted by specific LNAA supplements. The study thus

  18. CRISPR RNA-guided FokI nucleases repair a PAH variant in a phenylketonuria model

    PubMed Central

    Pan, Yi; Shen, Nan; Jung-Klawitter, Sabine; Betzen, Christian; Hoffmann, Georg F.; Hoheisel, Jörg D.; Blau, Nenad

    2016-01-01

    The CRISPR/Cas9 system is a recently developed genome editing technique. In this study, we used a modified CRISPR system, which employs the fusion of inactive Cas9 (dCas9) and the FokI endonuclease (FokI-dCas9) to correct the most common variant (allele frequency 21.4%) in the phenylalanine hydroxylase (PAH) gene - c.1222C>T (p.Arg408Trp) - as an approach toward curing phenylketonuria (PKU). PKU is the most common inherited diseases in amino acid metabolism. It leads to severe neurological and neuropsychological symptoms if untreated or late diagnosed. Correction of the disease-causing variants could rescue residual PAH activity and restore normal function. Co-expression of a single guide RNA plasmid, a FokI-dCas9-zsGreen1 plasmid, and the presence of a single-stranded oligodeoxynucleotide in PAH_c.1222C>T COS-7 cells – an in vitro model for PKU – corrected the PAH variant and restored PAH activity. Also in this system, the HDR enhancer RS-1 improved correction efficiency. This proof-of-concept indicates the potential of the FokI-dCas9 system for precision medicine, in particular for targeting PKU and other monogenic metabolic diseases. PMID:27786189

  19. Qualitative analysis of factors affecting adherence to the phenylketonuria diet in adolescents.

    PubMed

    Sharman, Rachael; Mulgrew, Kate; Katsikitis, Mary

    2013-01-01

    Phenylketonuria (PKU) is an inborn error of metabolism that is primarily treated with a severely restricted, low-protein diet to prevent permanent neurological damage. Despite the recognition of the importance of strict dietary adherence in the prevention of intellectual impairment in individuals with PKU, apathy and attrition from diet, especially during adolescence, remain a threat to normal development in this population. This study's aim was to examine adolescents' perception of factors that encourage or inhibit their dietary adherence. This was a qualitative study, with the authors using thematic analysis to interpret the findings. The study was conducted as part of a Metabolic Disorders Association conference. Eight adolescents with PKU were recruited through convenience sampling. A focus group was conducted with the adolescents to gather information about factors that encourage and discourage dietary adherence. Thematic analysis revealed that the adolescents encountered problems explaining the nature and food requirements of their condition to other people. Friends, family, and wanting to maintain "normal" cognitive abilities were identified as factors that encouraged dietary adherence. Adolescents with PKU appear to share several barriers and incentives for maintaining the strict dietary regimen. Considering such perceptions may aid future interventions aiming to reduce diet attrition rates among adolescents.

  20. CRISPR RNA-guided FokI nucleases repair a PAH variant in a phenylketonuria model.

    PubMed

    Pan, Yi; Shen, Nan; Jung-Klawitter, Sabine; Betzen, Christian; Hoffmann, Georg F; Hoheisel, Jörg D; Blau, Nenad

    2016-10-27

    The CRISPR/Cas9 system is a recently developed genome editing technique. In this study, we used a modified CRISPR system, which employs the fusion of inactive Cas9 (dCas9) and the FokI endonuclease (FokI-dCas9) to correct the most common variant (allele frequency 21.4%) in the phenylalanine hydroxylase (PAH) gene - c.1222C>T (p.Arg408Trp) - as an approach toward curing phenylketonuria (PKU). PKU is the most common inherited diseases in amino acid metabolism. It leads to severe neurological and neuropsychological symptoms if untreated or late diagnosed. Correction of the disease-causing variants could rescue residual PAH activity and restore normal function. Co-expression of a single guide RNA plasmid, a FokI-dCas9-zsGreen1 plasmid, and the presence of a single-stranded oligodeoxynucleotide in PAH_c.1222C>T COS-7 cells - an in vitro model for PKU - corrected the PAH variant and restored PAH activity. Also in this system, the HDR enhancer RS-1 improved correction efficiency. This proof-of-concept indicates the potential of the FokI-dCas9 system for precision medicine, in particular for targeting PKU and other monogenic metabolic diseases.

  1. [Phenylketonuria--toward a better carry-over care].

    PubMed

    Yoshino, Makoto; Watanabe, Yoriko; Ohira, Tomoko; Harada, Naomi

    2010-01-01

    Issues pertinent to patients with phenylketonuria(PKU) in adulthood are presented. Nutritional management policy that is optimal to prevent such nutritional complications as osteoporosis and possible vitamin B12 deficiency in each age group should be considered. Adolescent girls with PKU and their guardians should be informed of the issue of maternal PKU to prevent the condition. Socioeconomical issues also remain to be solved. Most adult patients have felt that medical expense to continue dietary therapy is a significant economical burden, which often leads to withdrawal from the therapy. Buying life insurance may be refused by insurance companies simply because the patients have PKU. Current knowledge on health status of well-controlled PKU patients should be provided to insurance companies.

  2. The Long-Term Use of a Low-Phenylalanine Diet in Late-Treated Phenylketonuria: A Single Case Report

    ERIC Educational Resources Information Center

    Hewitt, Philippa; Cottle, Mandy; Coleman, Carol

    2006-01-01

    Background: When phenylketonuria (PKU) is not diagnosed and long-term treatment commenced within the first few weeks of life, permanent brain damage will occur. There is some evidence to show that late diagnosed or untreated people with PKU who have severe challenging behaviours may benefit from a low phenylalanine diet [Harper & Reid (1987)…

  3. The Long-Term Use of a Low-Phenylalanine Diet in Late-Treated Phenylketonuria: A Single Case Report

    ERIC Educational Resources Information Center

    Hewitt, Philippa; Cottle, Mandy; Coleman, Carol

    2006-01-01

    Background: When phenylketonuria (PKU) is not diagnosed and long-term treatment commenced within the first few weeks of life, permanent brain damage will occur. There is some evidence to show that late diagnosed or untreated people with PKU who have severe challenging behaviours may benefit from a low phenylalanine diet [Harper & Reid (1987)…

  4. Commitment to Breastfeeding in the Context of Phenylketonuria.

    PubMed

    Banta-Wright, Sandra A; Kodadek, Sheila M; Houck, Gail M; Steiner, Robert D; Knafl, Kathleen A

    2015-01-01

    To describe the meaning and importance of breastfeeding to mothers of infants with phenylketonuria (PKU). Qualitative description. Mothers from the United States and Canada were recruited from the PKU Listserv and interviewed by telephone. Ten breastfeeding mothers with infants who had PKU and were younger than age 36 months. Mothers' thoughts, decisions, and experiences of breastfeeding their infants with PKU were collected through telephone interviews. Interviews were transcribed verbatim, and data were analyzed using thematic descriptive analysis in the context of PKU. Participants felt that that breastfeeding an infant with PKU was the healthiest choice and was therefore worth the labor. These women believed that this was what a loving mother would choose. As they continued to breastfeed their infants after diagnosis, the views of the participants changed. Initially they saw PKU as a disorder and felt that their infants were ill; later they felt that their infants were healthy in spite of PKU. Normal could mean a breastfeeding infant with PKU. Findings demonstrate the importance mothers attribute to breastfeeding and their willingness to invest considerable effort to breastfeed. Health care providers working with these mothers should help them strategize for success. © 2015 AWHONN, the Association of Women's Health, Obstetric and Neonatal Nurses.

  5. Congenital and Neurological Abnormalities in Infants with Phenylketonuria

    ERIC Educational Resources Information Center

    Johnson, Charles F.; And Others

    1978-01-01

    Examined was the occurrence of congenital and neurological abnormalities in 150 children with phenylketonuria (PKU--a metabolic disorder which may result in mental retardation) age 1 year or older, who have been treated with a restricted phenylalanine diet, according to the protocol used in a nation-wide longitudinal collaborative study.…

  6. Congenital and Neurological Abnormalities in Infants with Phenylketonuria

    ERIC Educational Resources Information Center

    Johnson, Charles F.; And Others

    1978-01-01

    Examined was the occurrence of congenital and neurological abnormalities in 150 children with phenylketonuria (PKU--a metabolic disorder which may result in mental retardation) age 1 year or older, who have been treated with a restricted phenylalanine diet, according to the protocol used in a nation-wide longitudinal collaborative study.…

  7. Sleep Disturbances in Phenylketonuria: An Explorative Study in Men and Mice

    PubMed Central

    Bruinenberg, Vibeke M.; Gordijn, Marijke C. M.; MacDonald, Anita; van Spronsen, Francjan J.; Van der Zee, Eddy A.

    2017-01-01

    Sleep problems have not been directly reported in phenylketonuria (PKU). In PKU, the metabolic pathway of phenylalanine is disrupted, which, among others, causes deficits in the neurotransmitters and sleep modulators dopamine, norepinephrine, and serotonin. Understanding sleep problems in PKU patients may help explain the pathophysiology of brain dysfunction in PKU patients. In this explorative study, we investigated possible sleep problems in adult treated PKU patients and untreated PKU mice. In the PKU patients, sleep characteristics were compared to healthy first degree relatives by assessment of sleep disturbances, sleep–wake patterns, and sleepiness with the help of four questionnaires: Holland sleep disorder questionnaire, Pittsburgh sleep quality index, Epworth sleepiness scale, and Munich Chronotype Questionnaire. The results obtained with the questionnaires show that PKU individuals suffer more from sleep disorders, a reduced sleep quality, and an increased latency to fall asleep and experience more sleepiness during the day. In the PKU mice, activity patterns were recorded with passive infrared recorders. PKU mice switched more often between active and non-active behavior and shifted a part of their resting behavior into the active period, confirming that sleep quality is affected as a consequence of PKU. Together, these results give the first indication that sleep problems are present in PKU. More detailed future research will give a better understanding of these problems, which could ultimately result in the improvement of treatment strategies by including sleep quality as an additional treatment target. PMID:28491049

  8. Phenylketonuria: nutritional advances and challenges

    PubMed Central

    2012-01-01

    Despite the appearance of new treatment, dietary approach remains the mainstay of PKU therapy. The nutritional management has become complex to optimize PKU patients' growth, development and diet compliance. This paper review critically new advances and challenges that have recently focused attention on potential relevant of LCPUFA supplementation, progress in protein substitutes and new protein sources, large neutral amino acids and sapropterin. Given the functional effects, DHA is conditionally essential substrates that should be supplied with PKU diet in infancy but even beyond. An European Commission Programme is going on to establish quantitative DHA requirements in this population. Improvements in the palatability, presentation, convenience and nutritional composition of protein substitutes have helped to improve long-term compliance with PKU diet, although it can be expected for further improvement in this area. Glycomacropeptide, a new protein source, may help to support dietary compliance of PKU subject but further studies are needed to evaluate this metabolic and nutritional issues. The PKU diet is difficult to maintain in adolescence and adult life. Treatment with large neutral amino acids or sapropterin in selected cases can be helpful. However, more studies are necessary to investigate the potential role, dose, and composition of large neutral amino acids in PKU treatment and to show long-term efficacy and tolerance. Ideally treatment with sapropterin would lead to acceptable blood Phe control without dietary treatment but this is uncommon and sapropterin will usually be given in combination with dietary treatment, but clinical protocol evaluating adjustment of PKU diet and sapropterin dosage are needed. In conclusion PKU diet and the new existing treatments, that need to be optimized, may be a complete and combined strategy possibly positive impacting on the psychological, social, and neurocognitive life of PKU patients. PMID:22305125

  9. Phenylketonuria: translating research into novel therapies

    PubMed Central

    Ho, Gladys

    2014-01-01

    Phenylketonuria (PKU) is an inborn error of metabolism of the amino acid phenylalanine. It is an autosomal recessive disorder with a rate of incidence of 1 in 10,000 in Caucasian populations. Mutations in the phenylalanine hydroxylase (PAH) gene are the major cause of PKU, due to the loss of the catalytic activity of the enzyme product PAH. Newborn screening for PKU allows early intervention, avoiding irreparable neurological damage and intellectual disability that would arise from untreated PKU. The current primary treatment of PKU is the limitation of dietary protein intake, which in the long term may be associated with poor compliance in some cases and other health problems due to malnutrition. The only alternative therapy currently approved is the supplementation of BH4, the requisite co-factor of PAH, in the orally-available form of sapropterin dihydrochloride. This treatment is not universally available, and is only effective for a proportion (estimated 30%) of PKU patients. Research into novel therapies for PKU has taken many different approaches to address the lack of PAH activity at the core of this disorder: enzyme replacement via virus-mediated gene transfer, transplantation of donor liver and recombinant PAH protein, enzyme substitution using phenylalanine ammonia lyase (PAL) to provide an alternative pathway for the metabolism of phenylalanine, and restoration of native PAH activity using chemical chaperones and nonsense read-through agents. It is hoped that continuing efforts into these studies will translate into a significant improvement in the physical outcome, as well as quality of life, for patients with PKU. PMID:26835324

  10. [Assessment of the life quality in children with phenylketonuria].

    PubMed

    Bushueva, T V; Vinyarskaya, I V; Chernikov, V V; Borovik, T E; Kuzenkova, L M

    2014-01-01

    Phenylketonuria (PKU) - the most common inherited disorder of amino acid metabolism, identified in Russia by neonatal screening. The results of dietary treatment demonstrate a positive effect. However, the quality of PKU patients life remains unknown. The aim of the study was to assess the quality of PKU children life in comparison with their healthy peers, also depending on the treatment onset and the patient's age. The study involved 64 pairs - PKU child and one of his parents. It was used the common questionnaire survey Pediatric Quality of Life Inventory (PedsQLtm4. 0, Varni et al., USA, 2001) and the program SPSS v. 14.0 (US) for statistical processing of the results. The statistically significant (p <0.001) differences between PKU patients and healthy children in the physical, emotional, social and role functioning were found. The most pronounced differences were observed in the social (70 points vs 90 respectively) and role (57.5 vs 80 respectively) functioning. Maximum significant correlation (p <0.001) was installed between the social functioning of PKU patients and timing of the dietary treatment. Also the statistically significant interaction (p <0.05) was found between the role functioning, patient's age and treatment onset. The assessment points of social and role functioning were higher (p <0.05) in the PKU patients subgroup with early treatment initiation. These results confirmed the need of early diagnostics of PKU and initiation of dietary treatment, as well as the organization of timely psychological support for parents of sick children.

  11. Formulation and PEGylation optimization of the therapeutic PEGylated phenylalanine ammonia lyase for the treatment of phenylketonuria

    PubMed Central

    Bell, Sean M.; Wendt, Dan J.; Zhang, Yanhong; Long, Shinong; Tsuruda, Laurie; Zhao, Bin; Laipis, Phillip; Fitzpatrick, Paul A.

    2017-01-01

    Phenylketonuria (PKU) is a genetic metabolic disease in which the decrease or loss of phenylalanine hydroxylase (PAH) activity results in elevated, neurotoxic levels of phenylalanine (Phe). Due to many obstacles, PAH enzyme replacement therapy is not currently an option. Treatment of PKU with an alternative enzyme, phenylalanine ammonia lyase (PAL), was first proposed in the 1970s. However, issues regarding immunogenicity, enzyme production and mode of delivery needed to be overcome. Through the evaluation of PAL enzymes from multiple species, three potential PAL enzymes from yeast and cyanobacteria were chosen for evaluation of their therapeutic potential. The addition of polyethylene glycol (PEG, MW = 20,000), at a particular ratio to modify the protein surface, attenuated immunogenicity in an animal model of PKU. All three PEGylated PAL candidates showed efficacy in a mouse model of PKU (BTBR Pahenu2) upon subcutaneous injection. However, only PEGylated Anabaena variabilis (Av) PAL-treated mice demonstrated sustained low Phe levels with weekly injection and was the only PAL evaluated that maintained full enzymatic activity upon PEGylation. A PEGylated recombinant double mutant version of AvPAL (Cys503Ser/Cys565Ser), rAvPAL-PEG, was selected for drug development based on its positive pharmacodynamic profile and favorable expression titers. PEGylation was shown to be critical for rAvPAL-PEG efficacy as under PEGylated rAvPAL had a lower pharmacodynamic effect. rAvPAL and rAvPAL-PEG had poor stability at 4°C. L-Phe and trans-cinnamate were identified as activity stabilizing excipients. rAvPAL-PEG is currently in Phase 3 clinical trials to assess efficacy in PKU patients. PMID:28282402

  12. Formulation and PEGylation optimization of the therapeutic PEGylated phenylalanine ammonia lyase for the treatment of phenylketonuria.

    PubMed

    Bell, Sean M; Wendt, Dan J; Zhang, Yanhong; Taylor, Timothy W; Long, Shinong; Tsuruda, Laurie; Zhao, Bin; Laipis, Phillip; Fitzpatrick, Paul A

    2017-01-01

    Phenylketonuria (PKU) is a genetic metabolic disease in which the decrease or loss of phenylalanine hydroxylase (PAH) activity results in elevated, neurotoxic levels of phenylalanine (Phe). Due to many obstacles, PAH enzyme replacement therapy is not currently an option. Treatment of PKU with an alternative enzyme, phenylalanine ammonia lyase (PAL), was first proposed in the 1970s. However, issues regarding immunogenicity, enzyme production and mode of delivery needed to be overcome. Through the evaluation of PAL enzymes from multiple species, three potential PAL enzymes from yeast and cyanobacteria were chosen for evaluation of their therapeutic potential. The addition of polyethylene glycol (PEG, MW = 20,000), at a particular ratio to modify the protein surface, attenuated immunogenicity in an animal model of PKU. All three PEGylated PAL candidates showed efficacy in a mouse model of PKU (BTBR Pahenu2) upon subcutaneous injection. However, only PEGylated Anabaena variabilis (Av) PAL-treated mice demonstrated sustained low Phe levels with weekly injection and was the only PAL evaluated that maintained full enzymatic activity upon PEGylation. A PEGylated recombinant double mutant version of AvPAL (Cys503Ser/Cys565Ser), rAvPAL-PEG, was selected for drug development based on its positive pharmacodynamic profile and favorable expression titers. PEGylation was shown to be critical for rAvPAL-PEG efficacy as under PEGylated rAvPAL had a lower pharmacodynamic effect. rAvPAL and rAvPAL-PEG had poor stability at 4°C. L-Phe and trans-cinnamate were identified as activity stabilizing excipients. rAvPAL-PEG is currently in Phase 3 clinical trials to assess efficacy in PKU patients.

  13. A cross-sectional study of docosahexaenoic acid status and cognitive outcomes in females of reproductive age with phenylketonuria

    PubMed Central

    Yi, Sarah H. L.; Kable, Julie A.; Evatt, Marian L.

    2014-01-01

    Diet therapy for phenylketonuria (PKU) requires restricted phenylalanine (Phe) intake, with the majority of protein and other nutrients coming from synthetic medical food. The fatty acid docosahexaenoic acid (DHA) is important in brain development and function; however, there are reports of low blood DHA concentrations in people treated for PKU. Although the implications of this low blood DHA are unclear, subtle cognitive deficits have been reported in those treated early and continuously for PKU. For this study, we investigated the relationship between DHA status and cognitive performance in 41 females 12 years and older with PKU. Participants were attending the baseline visit of a research-based camp or a supplementation trial. We assessed the domains of verbal ability, processing speed, and executive function using standardized tests, and the proportions of DHA in plasma and red blood cell (RBC) total lipids using gas chromatography/mass spectrometry. Percent plasma and RBC total lipid DHA were significantly lower in the participants compared with laboratory controls (P < .001), and participants consumed no appreciable DHA according to diet records. Plasma and RBC DHA both negatively correlated with plasma Phe (P < .02), and performance on the verbal ability task positively correlated with RBC DHA controlling for plasma Phe (R=.32, P=.03). The relationship between DHA and domains related to verbal ability, such as learning and memory, should be confirmed in a controlled trial. Domains of processing speed and executive function may require a larger sample size to clarify any association with DHA. PMID:21305356

  14. A cross-sectional study of docosahexaenoic acid status and cognitive outcomes in females of reproductive age with phenylketonuria.

    PubMed

    Yi, Sarah H L; Kable, Julie A; Evatt, Marian L; Singh, Rani H

    2011-04-01

    Diet therapy for phenylketonuria (PKU) requires restricted phenylalanine (Phe) intake, with the majority of protein and other nutrients coming from synthetic medical food. The fatty acid docosahexaenoic acid (DHA) is important in brain development and function; however, there are reports of low blood DHA concentrations in people treated for PKU. Although the implications of this low blood DHA are unclear, subtle cognitive deficits have been reported in those treated early and continuously for PKU. For this study, we investigated the relationship between DHA status and cognitive performance in 41 females 12 years and older with PKU. Participants were attending the baseline visit of a research-based camp or a supplementation trial. We assessed the domains of verbal ability, processing speed, and executive function using standardized tests, and the proportions of DHA in plasma and red blood cell (RBC) total lipids using gas chromatography/mass spectrometry. Percent plasma and RBC total lipid DHA were significantly lower in the participants compared with laboratory controls (P < .001), and participants consumed no appreciable DHA according to diet records. Plasma and RBC DHA both negatively correlated with plasma Phe (P < .02), and performance on the verbal ability task positively correlated with RBC DHA controlling for plasma Phe (R = .32, P = .03). The relationship between DHA and domains related to verbal ability, such as learning and memory, should be confirmed in a controlled trial. Domains of processing speed and executive function may require a larger sample size to clarify any association with DHA.

  15. The challenges of managing coexistent disorders with phenylketonuria: 30 cases.

    PubMed

    MacDonald, A; Ahring, K; Almeida, M F; Belanger-Quintana, A; Blau, N; Burlina, A; Cleary, M; Coskum, T; Dokoupil, K; Evans, S; Feillet, F; Giżewska, M; Gokmen Ozel, H; Lotz-Havla, A S; Kamieńska, E; Maillot, F; Lammardo, A M; Muntau, A C; Puchwein-Schwepcke, A; Robert, M; Rocha, J C; Santra, S; Skeath, R; Strączek, K; Trefz, F K; van Dam, E; van Rijn, M; van Spronsen, F; Vijay, S

    2015-12-01

    The few published case reports of co-existent disease with phenylketonuria (PKU) are mainly genetic and familial conditions from consanguineous marriages. The clinical and demographic features of 30 subjects with PKU and co-existent conditions were described in this multi-centre, retrospective cohort study. Diagnostic age of PKU and co-existent condition, treatment regimen, and impact of co-existent condition on blood phenylalanine (Phe) control and PKU management were reported. 30 patients (11 males and 19 females), with PKU and a co-existent condition, current median age of 14 years (range 0.4 to 40 years) from 13 treatment centres from Europe and Turkey were described. There were 21 co-existent conditions with PKU; 9 were autoimmune; 6 gastrointestinal, 3 chromosomal abnormalities, and 3 inherited conditions. There were only 5 cases of parental consanguinity. Some patients required conflicting diet therapy (n=5), nutritional support (n=7) and 5 children had feeding problems. There was delayed diagnosis of co-existent conditions (n=3); delayed treatment of PKU (n=1) and amenorrhea associated with Grave's disease that masked a PKU pregnancy for 12 weeks. Co-existent conditions adversely affected blood Phe control in 47% (n=14) of patients. Some co-existent conditions increased the complexity of disease management and increased management burden for patients and caregivers. Occurrence of co-existent disease is not uncommon in patients with PKU and so investigation for co-existent disorders when the clinical history is not completely consistent with PKU is essential. Integrating care of a second condition with PKU management is challenging. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. A case of maternal phenylketonuria syndrome presenting with unilateral renal agenesis.

    PubMed

    Gokmen, Tulin; Oguz, Serife Suna; Altug, Nahide; Akar, Melek; Erdeve, Omer; Dilmen, Ugur

    2011-04-01

    Maternal phenylketonuria (mPKU) during pregnancy leads to the risk of spontaneous abortion or a teratogenic syndrome depending on the level of maternal phenylalaninemia. Mental retardation, microcephaly, congenital cardiopathy and intrauterine growth retardation are frequently seen in patients who intake an unrestricted diet before conception. The clinical picture shows variation in classic PKU. Severe neurological symptoms are not seen in all untreated cases of PKU syndromes. For this reason, mPKU can be seen in undiagnosed mothers. We hereby present a case who underwent investigations due to the presence of microcephaly and congenital cardiopathy. The diagnosis of PKU syndrome of the mother was determined following assessment of the baby. Furthermore, the unilateral renal agenesis that was detected in our case is the first case reported in the literature in which mPKU accompanies renal agenesis.

  17. Genetics of Phenylketonuria: Then and Now.

    PubMed

    Blau, Nenad

    2016-06-01

    More than 950 phenylalanine hydroxylase (PAH) gene variants have been identified in people with phenylketonuria (PKU). These vary in their consequences for the residual level of PAH activity, from having little or no effect to abolishing PAH activity completely. Advances in genotyping technology and the availability of locus-specific and genotype databases have greatly expanded our understanding of the correlations between individual gene variant, residual PAH activity, tetrahydrobiopterin (BH4 ) responsiveness, and the clinical PKU phenotype. Most patients (∼76%) have compound heterozygous PAH gene variants and one mutated allele may markedly influence the activity of the second mutated allele, which in turn may influence either positively or negatively the activity of the biologically active heterotetrameric form of the PAH. While it is possible to predict the level of BH4 responsiveness (∼71%) and PKU severity (∼78%) from the nature of the underlying gene variants, these relationships remain complex and incompletely understood. A greater understanding of these relationships may increase the potential for individualized management of PKU in future. Inherited deficiencies in BH4 metabolism account for about 1%-2% of all hyperphenylalaninemias and are clinically more severe than PKU. Almost 90% of all patients are deficient in 6-pyruvoyl-tetrahydropterin synthase and dihydropteridine reductase.

  18. Developmental defects of enamel in phenylketonuria patients.

    PubMed

    de Marco Salvadori, Carina; Pereira, Rosana Marques; Raichert, Caroline; de Morais Ferreira, Fernanda; de Menezes, José Vitor Nogara Borges

    2014-01-01

    The purpose of this study was to determine the prevalence of developmental defects of enamel in patients diagnosed with phenylketonuria (PKU). The study group consisted of 24 four- to 24-year-old subjects with PKU. The control group consisted of 24 healthy individuals. An examination for the detection of developmental defects of enamel was conducted at the university pediatric dentistry clinic by a single examiner. Data were analyzed using the chi-square test (P<.05) and odds ratios. The prevalence of developmental defects of enamel was 36 percent in the study group and 15 percent in the control group. The maxillary central incisors were the most affected teeth in patients with PKU, while the maxillary and mandibular first molars were the most affected teeth in the control group. Patients with PKU had a 3.3-fold greater chance of exhibiting developmental defects of enamel versus the healthy controls, which was statistically significant (P<.001). The study findings suggest that PKU increases the risk of developmental defects of enamel.

  19. Phenylalanine control and family functioning in early-treated phenylketonuria.

    PubMed

    Reber, M; Kazak, A E; Himmelberg, P

    1987-12-01

    The association between effective metabolic control and patients' intelligence test performance and behavior in phenylketonuria (PKU) has been demonstrated frequently. The present study reexamined this relationship in a population of 41 young children with early-treated PKU, and added a dimension of family investigation to determine relationships between dietary phenylalanine control and patient functioning, family functioning and phenylalanine control, and family functioning and patient functioning. Significant correlations were found between concurrent phenylalanine control and patients' intelligence test scores, and lifetime phenylalanine control and patients' social competence. Parent-report measures of family psychological adjustment, stress, interaction, and socioeconomic status showed no significant association with children's dietary phenylalanine control. Family cohesion and adaptability correlated positively with patients' cognitive performance. Results support a policy of diet continuation in PKU, and suggest that family interaction patterns influence patient functioning. Longitudinal study of family factors in PKU is indicated.

  20. Costs and Outcomes over 36 Years of Patients with Phenylketonuria Who Do and Do Not Remain on a Phenylalanine-Restricted Diet

    ERIC Educational Resources Information Center

    Guest, J. F.; Bai, J. J.; Taylor, R. R.; Sladkevicius, E.; Lee, P. J.; Lachmann, R. H.

    2013-01-01

    Background: To quantify the costs and consequences of managing phenylketonuria (PKU) in the UK and to estimate the potential implications to the UK's National Health Service (NHS) of keeping patients on a phenylalanine-restricted diet for life. Methods: A computer-based model was constructed depicting the management of PKU patients over the first…

  1. Costs and Outcomes over 36 Years of Patients with Phenylketonuria Who Do and Do Not Remain on a Phenylalanine-Restricted Diet

    ERIC Educational Resources Information Center

    Guest, J. F.; Bai, J. J.; Taylor, R. R.; Sladkevicius, E.; Lee, P. J.; Lachmann, R. H.

    2013-01-01

    Background: To quantify the costs and consequences of managing phenylketonuria (PKU) in the UK and to estimate the potential implications to the UK's National Health Service (NHS) of keeping patients on a phenylalanine-restricted diet for life. Methods: A computer-based model was constructed depicting the management of PKU patients over the first…

  2. Nutritional status of patients with phenylketonuria in Japan.

    PubMed

    Okano, Yoshiyuki; Hattori, Toshikazu; Fujimoto, Hiroki; Noi, Kaori; Okamoto, Miki; Watanabe, Toshiaki; Watanabe, Ryoko; Fujii, Rika; Tamaoki, Tomoko

    2016-09-01

    Accumulating evidence suggests that hyperphenylalaninemia in phenylketonuria (PKU) can cause neuropsychological and psychosocial problems in diet-off adult patients, and that such symptoms improve after resumption of phenylalanine-restricted diet, indicating the need for lifetime low-phenylalanine diet. While limiting protein intake, dietary therapy should provide adequate daily intake of energy, carbohydrates, fat, vitamins, and microelements. We evaluated nutrient balance in 14 patients with classical PKU aged 4-38 years. Approximately 80-85% of the recommended dietary allowance (RDA) of protein in Japanese was supplied through phenylalanine-free (Phe-free) milk and Phe-free amino acid substitutes. Nutritional evaluation showed that the calorie and protein intakes were equivalent to the RDA. Phenylalanine intake was 9.8 ± 2.2 mg/kg of body weight/day, which maintained normal blood phenylalanine concentration by the 80% Phe-free protein rule. The protein, fat, and carbohydrate ratio was 9.5:23.9:66.6% with relative carbohydrate excess. Phe-free milk and amino acid substitutes provided 33.7% of carbohydrate, 82.1% of protein, and 66.7% of fat intake in all. Selenium and biotin intakes were 25.0% and 18.1% of the RDA and adequate intake (AI) for Japanese, respectively; both were not included in Phe-free milk. PKU patients showed low serum selenium, low urinary biotin, and high urinary 3-hydroxyisovaleric acid in this study. The intakes of magnesium, zinc, and iodine were low (71.5%, 79.5%, and 71.0% of the RDA, respectively) and that of phosphorus was 79.7% of the AI, although they were supplemented in Phe-free milk. PKU patients depend on Phe-free milk and substitutes for daily requirement of microelements and vitamins as well as protein and fat. Development of low-protein food makes it possible to achieve the aimed phenylalanine blood level, but this lowers the intake of microelements and vitamins from natural foods. The dietary habits vary continuously with

  3. The complexity of newborn screening follow-up in phenylketonuria.

    PubMed

    Hecht, Leah E; Wessel, Ann E; Levy, Harvey L; Berry, Gerard T

    2014-01-01

    In the United States, and most developed nations, the newborn screening (NBS) panel covers many primary disorders of metabolism, including phenylketonuria (PKU). When an elevated phenylalanine level is identified, the infant is evaluated for PKU and should also be tested for tetrahydrobiopterin (BH4) deficiency. A neonate presented with a phenylalanine level of 254 μmol/L (reference range <138 μmol/L) on newborn screening. The infant's confirmatory phenylalanine was 118 μmol/L (reference range <77 μmol/L). Her urine pterin profile was normal, and initially she had no measurable activity of red blood cell (RBC) dihydropteridine reductase (DHPR). Subsequent study revealed normal levels of CSF tetrahydrobiopterin and neurotransmitter metabolites, and by 18 months of age, her RBC DHPR activity was detectable at 0.5 nmol/min/mgHgb (reference range 0.8-3.9). Sequencing of the QDPR gene for DHPR revealed c.1A>T nucleotide substitution in exon 3 expressed as "p.MET1?" Phenylalanine hydroxylase (PAH) gene sequencing revealed compound heterozygosity for L249F and A300S. Although initial testing suggested the child was affected with DHPR deficiency, further analysis, finding increasing levels of DHPR activity and PAH compound mutant heterozygosity, indicated that the primary disorder is mild hyperphenylalaninemia with carrier status for DHPR deficiency. This is an example of newborn screening results leading to confusing findings requiring extensive biochemical studies and genotyping in order to arrive at the appropriate diagnosis.

  4. Communicative and psycholinguistic abilities in children with phenylketonuria and congenital hypothyroidism

    PubMed Central

    GEJÃO, Mariana Germano; FERREIRA, Amanda Tragueta; SILVA, Greyce Kelly; ANASTÁCIO-PESSAN, Fernanda da Luz; LAMÔNICA, Dionísia Aparecida Cusin

    2009-01-01

    ABSTRACT The Neonatal Screening for Inborn Errors of Metabolism of the Association of Parents and Friends of Special Needs Individuals (APAE) - Bauru, Brazil, was implanted and accredited by the Brazilian Ministry of Health in 1998. It covers about 286 cities of the Bauru region and 420 collection spots. Their activities include screening, diagnosis, treatment and assistance to congenital hypothyroidism (CH) and phenylketonuria (PKU), among others. In 2005, a partnership was established with the Department of Speech-Language Pathology and Audiology, Bauru School of Dentistry, University of São Paulo, Bauru, seeking to characterize and to follow, by means of research studies, the development of the communicative abilities of children with CH and PKU. Objective: The aim of this study was to describe communicative and psycholinguistic abilities in children with CH and PKU. Materials and Methods: Sixty-eight children (25 children aged 1 to 120 months with PKU and 43 children aged 1 to 60 months with CH) participated in the study. The handbooks were analyzed and different instruments were applied (Observation of Communication Behavior, Early Language Milestone Scale, Peabody Picture Vocabulary Test, Gesell & Amatruda's Behavioral Development Scale, Portage Operation Inventory, Language Development Evaluation Scale, Denver Developmental Screening Test, ABFW Child Language Test-phonology and Illinois Test of Psycholinguistic Abilities), according to the children's age group and developmental level. Results: It was observed that the children with PKU and CH at risk for alterations in their developmental abilities (motor, cognitive, linguistic, adaptive and personal-social), mainly in the first years of life. Alterations in the psycholinguistic abilities were also found, mainly after the preschool age. Attention deficits, language and cognitive alterations were more often observed in children with CH, while attention deficits with hyperactivity and alterations in the

  5. Parenting a child with phenylketonuria or galactosemia: implications for health-related quality of life.

    PubMed

    ten Hoedt, Amber E; Maurice-Stam, Heleen; Boelen, Carolien C A; Rubio-Gozalbo, M Estela; van Spronsen, Francjan J; Wijburg, Frits A; Bosch, Annet M; Grootenhuis, Martha A

    2011-04-01

    Parents of children with chronic disorders have an impaired health-related quality of life (HRQoL) compared to parents of healthy children. Remarkably, parents of children with a metabolic disorder reported an even lower HRQoL than parents of children with other chronic disorders. Possibly, the uncertainty about the course of the disease and the limited life expectancy in many metabolic disorders are important factors in the low parental HRQoL. Therefore, we performed a cross-sectional study in parents of children with phenylketonuria (PKU, OMIM #261600) and galactosemia (OMIM #230400), metabolic disorders not affecting life expectancy, in order to investigate their HRQoL compared to parents of healthy children and to parents of children with other metabolic disorders. A total of 185 parents of children with PKU and galactosemia aged 1-19 years completed two questionnaires. Parents of children with PKU or galactosemia reported a HRQoL comparable to parents of healthy children and a significantly better HRQoL than parents of children with other metabolic disorders. Important predictors for parental mental HRQoL were the psychosocial factors emotional support and loss of friendship. As parental mental functioning influences the health, development and adjustment of their children, it is important that treating physicians also pay attention to the wellbeing of the parents. The insight that emotional support and loss of friendship influence the HRQoL of the parents enables treating physicians to provide better support for these parents.

  6. Breast-feeding success among infants with phenylketonuria.

    PubMed

    Banta-Wright, Sandra A; Shelton, Kathleen C; Lowe, Nancy D; Knafl, Kathleen A; Houck, Gail M

    2012-08-01

    Breast milk is the nutrition of choice for human infants (American Academy of Pediatrics, 2005; American Association of Family Physicians, 2008; Association of Women's Health Obstetric and Neonatal Nurses, 2005; Canadian Paediatric Society, 2005; U.S. Preventive Services Task Force, 2008; World Health Organization, 2009). In comparison to standard commercial formula, human breast milk has a lower concentration of protein and a lower content of the amino acid phenylalanine (Phe). For infants with phenylketonuria (PKU), these attributes of human breast milk make it ideal as a base source of nutrition. The purpose of this study was to compare the incidence and duration of breast-feeding and corresponding Phe levels of breast-fed and formula-fed infants with PKU in the caseload of a pediatric metabolic clinic at an urban tertiary-care medical center. Charts were reviewed for infants diagnosed with PKU beginning with 2005 and ending with 1980, the year no further breast-feeding cases were identified in the PKU population. During the first year of life, most of the infants, whether breast-fed or formula-fed, had similar mean Phe levels. However, the frequency distributions revealed that more breast-fed infants with PKU had Phe levels within the normal range (120-360 μmol/L) and were less likely to have low Phe levels (<120 μmol/L) than formula-fed infants with PKU. Further research is needed to understand how mothers manage breast-feeding in the context of PKU.

  7. Advances in the nutritional and pharmacological management of phenylketonuria

    PubMed Central

    Ney, Denise M.; Blank, Robert D.; Hansen, Karen E.

    2014-01-01

    Structural Abstract Purpose of review The purpose is to discuss advances in the nutritional and pharmacological management of phenylketonuria (PKU). Recent findings Glycomacropeptide (GMP), a whey protein produced during cheese production, is a low-phe intact protein that represents a new dietary alternative to synthetic amino acids (AAs) for people with PKU. Skeletal fragility is a long-term complication of PKU that based on murine research, appears to result from both genetic and nutritional factors. Skeletal fragility in murine PKU is attenuated with the GMP diet, compared with an AA diet, allowing greater radial bone growth. Pharmacologic therapy with tetrahydrobiopterin (BH4), acting as a molecular chaperone for phenylalanine hydroxylase, increases tolerance to dietary phe in some individuals. Large neutral AAs (LNAA) inhibit phe transport across the intestinal mucosa and blood brain barrier; LNAA are most effective for individuals unable to comply with the low-phe diet. Summary Although a low-phe synthetic AA diet remains the mainstay of PKU management, new nutritional and pharmacological treatment options offer alternative approaches to maintain lifelong low phe concentrations. GMP medical foods provide an alternative to AA formula that may improve bone health, and BH4 permits some individuals with PKU to increase tolerance to dietary phe. Further research is needed to characterize the long-term efficacy of these new approaches for PKU management. PMID:24136088

  8. Undiagnosed phenylketonuria in parents of phenylketonuric patients, is it worthwhile to be checked?

    PubMed

    Wiedemann, A; Leheup, B; Battaglia-Hsu, S-F; Jonveaux, P; Jeannesson, E; Feillet, F

    2013-01-01

    In our phenylketonuria (PKU) cohort of 120 patients, we uncovered a couple of cases of undiagnosed mild phenylketonuria (mPKU)/hyperphenylalaninemia (mHPA) in maternal parents of the PKU cohort. This finding prompted us to evaluate the risk of either mild phenylketonuria or mild hyperphenylalaninemia in the parent population whose children were diagnosed with hyperphenylalaninemia (HPA). Taking into account the phenylalanine hydroxylase (PAH) mutation carrier frequency and the PAH mild mutation rate, we estimated that the prevalence of the parental mPKU/mHPA varied widely, from 1/74 in Turkey to 1/708 in Lithuania. The benefits of the parental detection procedure described here are the prevention of further maternal PKU syndrome, the follow-up of the newly detected patients and the accuracy of the genetic counseling provided to these families. This very simple procedure should be incorporated into neonatal PKU management of the hospitals in countries where a routine systematic neonatal screening is operational. © 2013.

  9. The oxidative molecular regulation mechanism of NOX in children with phenylketonuria.

    PubMed

    He, Ying-Zhong; Gu, Xue-Fan; Lu, Li-Hua; Liang, Li-Li

    2014-11-01

    Phenylketonuria (PKU) is the most frequent inherited disorder of amino acid metabolism. In our previous work, we investigated the role of NADPH oxidase (NOX) in a Pahenu2-BTBR PKU mouse model, and an in vitro cell culture model of PKU. In the current study, we evaluated various oxidative stress parameters, namely total antioxidant capacity (T-AOC), glutathione (GSH) and maleic dialdehyde (MDA) in the plasma of 40 PKU children, for further investigating the oxidative molecular regulation mechanism of NOX in PKU. It was observed that T-AOC and GSH markedly decreased in PKU as compared with the control group (P<0.01), and seemed to correlate negatively with Phe level. However, there was no statistical difference in MDA level among the three groups. And 8-isoprostane in the blood samples of PKU2 groups was slightly higher than control group (P<0.05). Additionally, mRNA levels of subunits of NOX included p47(phox) and p67(phox) significantly increased in PKU group (P<0.01). These results reflected that NOX is the important source of reactive oxygen species and is involved in the oxidative molecular regulation mechanism in PKU, which shows a new perspective toward understanding the biological underpinnings of PKU. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

  10. Systematic Review and Meta-Analysis of Neuropsychiatric Symptoms and Executive Functioning in Adults With Phenylketonuria.

    PubMed

    Bilder, Deborah A; Noel, J Kay; Baker, Erin R; Irish, William; Chen, Yinpu; Merilainen, Markus J; Prasad, Suyash; Winslow, Barbara J

    2016-01-01

    This systematic review and meta-analysis (MA) investigates the impact of elevated blood phenylalanine (Phe) on neuropsychiatric symptoms in adults with phenylketonuria (PKU). The meta-analysis of PKU is challenging because high-quality evidence is lacking due to the limited number of affected individuals and few placebo-controlled, double-blind studies of adults with high and low blood Phe. Neuropsychiatric symptoms associated with PKU exceed general population estimates for inattention, hyperactivity, depression, and anxiety. High Phe is associated with an increased prevalence of neuropsychiatric symptoms and executive functioning deficits whereas low Phe is associated with improved neurological performance. Findings support lifelong maintenance of low blood Phe.

  11. [Neonatal screening for congenital hypothyroidism and phenylketonuria].

    PubMed

    Velázquez, A; Loera-Luna, A; Aguirre, B E; Gamboa, S; Vargas, H; Robles, C

    1994-01-01

    A newborn screening program for congenital hypothyroidism (CH) and phenylketonuria (PKU) was conducted in 140 163 infants from the Federal District and the states of Mexico and Tlaxcala. These children were born mainly in hospitals for the non-insured population, although some were social security beneficiaries. Their filter-paper blood TSH and phenylalanine concentrations were determined 48 hours after birth. The frequency of CH was 1:1 797, with a 95 per cent confidence interval of 1:1 470 to 1:2 315, and was quite similar in the different types of hospitals. Only two PKU cases were found, for a frequency of 1:70 082, with a 95 per cent confidence interval of 0 to 1:4 762. This work demonstrates the feasibility of newborn screening programs in Mexico, identifies the problems to be solved in order to achieve a wide coverage and establishes the high frequency of CH in the Mexican population.

  12. Multiple origins for phenylketonuria in Europe

    SciTech Connect

    Eisensmith, R.C.; Okano, Y.; Dasovich, M.; Wang, T.; Woo, S.L.C. ); Guettler, F.; Lou, H.; Guldberg, P. ); Lichter-Konecki, U.; Konecki, D.S. ); Svensson, E.; Hagenfeldt, L. ); Rey, F.; Munnich, A.; Lyonnet, S. ); Cockburn, F.; Connor, J.M. ); Pembrey, M.E.; Smith, I. ); Gitzelmann, R.; Steinmann, B. ); Apold, J.; Eiken, H.G. ); Giovannini, M.; Riva, E.; Longhi, R. ); Romano, C.; Cerone, R. ); Naughten, E.R.; Mullins, C.; Cahalane, S. ); Oezalp, I. )

    1992-12-01

    Phenylketonuria (PKU), a disorder of amino acid metabolism prevalent among Caucasians and other ethnic groups, is caused primarily by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH). PKU is a highly heterogeneous disorder, with more than 60 molecular lesions identified in the PAH gene. The haplotype associations, relative frequencies, and distributions of five prevalent PAH mutations (R158Q, R261Q, IVS10nt546, R408W, and IVS12nt1) were established in a comprehensive European sample population and subsequently were examined to determine the potential roles of several genetic mechanisms in explaining the present distribution of the major PKU alleles. Each of these five mutations was strongly associated with only one of the more than 70 chromosomal haplotypes defined by eight RFLPs in or near the PAH gene. These findings suggest that each of these mutations arose through a single founding event that occurred within time periods ranging from several hundred to several thousand years ago. From the significant differences observed in the relative frequencies and distributions of these five alleles throughout Europe, four of these putative founding events could be localized to specific ethnic subgroups. Together, these data suggest that there were multiple, geographically and ethnically distinct origins for PKU within the European population. 63 refs., 2 figs., 3 tabs.

  13. Early Screening for Tetrahydrobiopterin Responsiveness in Phenylketonuria.

    PubMed

    Porta, Francesco; Spada, Marco; Ponzone, Alberto

    2017-08-01

    Since 2007, synthetic tetrahydrobiopterin (BH4) has been approved as a therapeutic option in BH4-responsive phenylketonuria (PKU) and since 2015 extended to infants younger than 4 years in Europe. The current definition of BH4 responsiveness relies on the observation of a 20% to 30% blood phenylalanine (Phe) decrease after BH4 administration, under nonstandardized conditions. By this definition, however, patients with the same genotype or even the same patients were alternatively reported as responsive or nonresponsive to the cofactor. These inconsistencies are troubling, as frustrating patient expectations and impairing cost-effectiveness of BH4-therapy. Here we tried a quantitative procedure through the comparison of the outcome of a simple Phe and a combined Phe plus BH4 loading in a series of infants with PKU, most of them harboring genotypes already reported as BH4 responsive. Under these ideal conditions, blood Phe clearance did not significantly differ after the 2 types of loading, and a 20% to 30% decrease of blood Phe occurred irrespective of BH4 administration in milder forms of PKU. Such early screening for BH4 responsiveness, based on a quantitative assay, is essential for warranting an evidence-based and cost-effective therapy in those patients with PKU eventually but definitely diagnosed as responsive to the cofactor. Copyright © 2017 by the American Academy of Pediatrics.

  14. Multiple origins for phenylketonuria in Europe

    PubMed Central

    Eisensmith, R. C.; Okano, Y.; Dasovich, M.; Wang, T.; Güttler, F.; Lou, H.; Guldberg, P.; Lichter-Konecki, U.; Konecki, D. S.; Svensson, E.; Hagenfeldt, L.; Rey, F.; Munnich, A.; Lyonnet, S.; Cockburn, F.; Connor, J. M.; Pembrey, M. E.; Smith, I.; Gitzelmann, R.; Steinmann, B.; Apold, J.; Eiken, H. G.; Giovannini, M.; Riva, E.; Longhi, R.; Romano, C.; Cerone, R.; Naughten, E. R.; Mullins, C.; Cahalane, S.; Özalp, I.; Fekete, G.; Schuler, D.; Berencsi, G. Y.; Nász, I.; Brdicka, R.; Kamaryt, J.; Pijackova, A.; Cabalska, B.; Boszkowa, K.; Schwartz, E.; Kalinin, V. N.; Jin, L.; Chakraborty, R.; Woo, S. L. C.

    1992-01-01

    Phenylketonuria (PKU), a disorder of amino acid metabolism prevalent among Caucasians and other ethnic groups, is caused primarily by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH). PKU is a highly heterogeneous disorder, with more than 60 molecular lesions identified in the PAH gene. The haplotype associations, relative frequencies, and distributions of five prevalent PAH mutations (R158Q, R261Q, IVS10nt546, R408W, and IVS12nt1) were established in a comprehensive European sample population and subsequently were examined to determine the potential roles of several genetic mechanisms in explaining the present distribution of the major PKU alleles. Each of these five mutations was strongly associated with only one of the more than 70 chromosomal haplotypes defined by eight RFLPs in or near the PAH gene. These findings suggest that each of these mutations arose through a single founding event that occurred within time periods ranging from several hundred to several thousand years ago. From the significant differences observed in the relative frequencies and distributions of these five alleles throughout Europe, four of these putative founding events could be localized to specific ethnic subgroups. Together, these data suggest that there were multiple, geographically and ethnically distinct origins for PKU within the European population. PMID:1361100

  15. Phenylketonuria: reduced tyrosine brain influx relates to reduced cerebral protein synthesis

    PubMed Central

    2013-01-01

    Background In phenylketonuria (PKU), elevated blood phenylalanine (Phe) concentrations are considered to impair transport of large neutral amino acids (LNAAs) from blood to brain. This impairment is believed to underlie cognitive deficits in PKU via different mechanisms, including reduced cerebral protein synthesis. In this study, we investigated the hypothesis that impaired LNAA influx relates to reduced cerebral protein synthesis. Methods Using positron emission tomography, L-[1-11C]-tyrosine (11C-Tyr) brain influx and incorporation into cerebral protein were studied in 16 PKU patients (median age 24, range 16 – 47 years), most of whom were early and continuously treated. Data were analyzed by regression analyses, using either 11C-Tyr brain influx or 11C-Tyr cerebral protein incorporation as outcome variable. Predictor variables were baseline plasma Phe concentration, Phe tolerance, age, and 11C-Tyr brain efflux. For the modelling of cerebral protein incorporation, 11C-Tyr brain influx was added as a predictor variable. Results 11C-Tyr brain influx was inversely associated with plasma Phe concentrations (median 512, range 233 – 1362 μmol/L; delta adjusted R2=0.571, p=0.013). In addition, 11C-Tyr brain influx was positively associated with 11C-Tyr brain efflux (delta adjusted R2=0.098, p=0.041). Cerebral protein incorporation was positively associated with 11C-Tyr brain influx (adjusted R2=0.567, p<0.001). All additional associations between predictor and outcome variables were statistically nonsignificant. Conclusions Our data favour the hypothesis that an elevated concentration of Phe in blood reduces cerebral protein synthesis by impairing LNAA transport from blood to brain. Considering the importance of cerebral protein synthesis for adequate brain development and functioning, our results support the notion that PKU treatment be continued in adulthood. Future studies investigating the effects of impaired LNAA transport on cerebral protein synthesis in

  16. Morphometric analysis of gray matter integrity in individuals with early-treated phenylketonuria.

    PubMed

    Christ, Shawn E; Price, Mason H; Bodner, Kimberly E; Saville, Christopher; Moffitt, Amanda J; Peck, Dawn

    2016-05-01

    The most widely-reported neurologic finding in individuals with early-treated phenylketonuria (PKU) is abnormality in the white matter of the brain. In contrast, much less is known regarding the impact of PKU on cortical gray matter (GM) structures. Presently, we applied advanced morphometric methods to the analysis of high-resolution structural MRI images from a sample of 19 individuals with early-treated PKU and an age- and gender-matched comparison group of 22 healthy individuals without PKU. Data analysis revealed decreased GM volume in parietal cortex for the PKU group compared with the non-PKU group. A similar trend was observed for occipital GM volume. There was no evidence of group-related differences in frontal or temporal GM volume. Within the PKU group, we also found a significant relationship between blood phenylalanine levels and GM volume for select posterior cortical sub-regions. Taken together with previous research on white matter and gray matter abnormalities in PKU, the present findings point to the posterior cortices as the primary site of neurostructural changes related to early-treated PKU.

  17. Intellectual Assessment of 111 Four-Year-Old Children with Phenylketonuria

    ERIC Educational Resources Information Center

    Dobson, James C.; And Others

    1977-01-01

    Available from: Arthur Retlaw and Associates, Inc., Suite 2080, 1603 Orrington Avenue, Evanston, Illinois 60201. A sample of 4-year-old children (n=111) with PKU (phenylketonuria) who were placed on dietary therapy between 3 and 92 days of age were assigned to two treatment groups based on "moderate" and "low" serum…

  18. PHENYLKETONURIA, DETECTION IN THE NEWBORN INFANT AS A ROUTINE HOSPITAL PROCEDURE.

    ERIC Educational Resources Information Center

    GUTHRIE, ROBERT; WHITNEY, STEWART

    A FIELD TRIAL OF AN INHIBITION ASSAY METHOD FOR SCREENING FOR PHENYLKETONURIA (PKU) TESTED MORE THAN 400,000 NEWBORN INFANTS PRIOR TO DISCHARGE FROM THE HOSPTIAL. IN ALL, 39 CASES WERE FOUND, A HIGHER INCIDENCE THAN HAD PREVIOUSLY BEEN EXPECTED. THE PRACTICALITY OF THE INHIBITION ASSAY METHOD WAS ALSO DEMONSTRATED. THE REPORT DETAILS THE TRIAL'S…

  19. Loss of Intellectual Function in Children with Phenylketonuria after Relaxation of Dietary Phenylalanine Restriction.

    ERIC Educational Resources Information Center

    Seashore, Margretta R.; And Others

    1985-01-01

    Discontinuation at ages five to six of dietary restriction in 14 children with classic phenylketonuria (PKU--a metabolic disorder which, if untreated, is associated with mental retardation) resulted in deterioration in intellectual function for some of the Ss. Deficits included visual motor integration and cognitive problem solving. (CL)

  20. Intellectual Assessment of 111 Four-Year-Old Children with Phenylketonuria

    ERIC Educational Resources Information Center

    Dobson, James C.; And Others

    1977-01-01

    Available from: Arthur Retlaw and Associates, Inc., Suite 2080, 1603 Orrington Avenue, Evanston, Illinois 60201. A sample of 4-year-old children (n=111) with PKU (phenylketonuria) who were placed on dietary therapy between 3 and 92 days of age were assigned to two treatment groups based on "moderate" and "low" serum…

  1. PHENYLKETONURIA, DETECTION IN THE NEWBORN INFANT AS A ROUTINE HOSPITAL PROCEDURE.

    ERIC Educational Resources Information Center

    GUTHRIE, ROBERT; WHITNEY, STEWART

    A FIELD TRIAL OF AN INHIBITION ASSAY METHOD FOR SCREENING FOR PHENYLKETONURIA (PKU) TESTED MORE THAN 400,000 NEWBORN INFANTS PRIOR TO DISCHARGE FROM THE HOSPTIAL. IN ALL, 39 CASES WERE FOUND, A HIGHER INCIDENCE THAN HAD PREVIOUSLY BEEN EXPECTED. THE PRACTICALITY OF THE INHIBITION ASSAY METHOD WAS ALSO DEMONSTRATED. THE REPORT DETAILS THE TRIAL'S…

  2. Loss of Intellectual Function in Children with Phenylketonuria after Relaxation of Dietary Phenylalanine Restriction.

    ERIC Educational Resources Information Center

    Seashore, Margretta R.; And Others

    1985-01-01

    Discontinuation at ages five to six of dietary restriction in 14 children with classic phenylketonuria (PKU--a metabolic disorder which, if untreated, is associated with mental retardation) resulted in deterioration in intellectual function for some of the Ss. Deficits included visual motor integration and cognitive problem solving. (CL)

  3. White Matter Integrity and Executive Abilities in Individuals with Phenylketonuria

    PubMed Central

    Antenor-Dorsey, Jo Ann V.; Hershey, Tamara; Rutlin, Jerrel; Shimony, Joshua S.; McKinstry, Robert C.; Grange, Dorothy K.; Christ, Shawn E.; White, Desirée A.

    2013-01-01

    Previous studies have revealed white matter abnormalities in the brains of individuals with phenylketonuria (PKU), but the microstructural nature of these abnormalities and their relationship to phenylalanine (Phe) levels and cognitive outcomes is poorly understood. In the current study, the microstructural integrity of white matter in 29 individuals with early-treated PKU and 12 healthy controls was examined using two complementary diffusion tensor imaging (DTI) approaches: region-of-interest (ROI) based analysis and voxel-wise tract based spatial statistics (TBSS) analysis. Relationships among DTI, executive abilities, and Phe level findings were explored. DTI revealed widespread lowering of mean diffusivity (MD) in the white matter of the PKU group in comparison with the control group. Executive abilities were also poorer for individuals with PKU than controls. Within the PKU group, lower MD was associated with higher Phe level and poorer executive abilities. These findings are the first to demonstrate the interplay among microstructural white matter integrity, executive abilities, and Phe control in individuals with PKU. PMID:23608077

  4. Up to date knowledge on different treatment strategies for phenylketonuria

    PubMed Central

    Bélanger-Quintana, Amaya; Burlina, Alberto; Harding, Cary O.; Muntau, Ania C.

    2015-01-01

    Dietary management for phenylketonuria was established over half a century ago, and has rendered an immense success in the prevention of the severe mental retardation associated with the accumulation of phenylalanine. However, the strict low-phenylalanine diet has several shortcomings, not the least of which is the burden it imposes on the patients and their families consequently frequent dietary non-compliance. Imperfect neurological outcome of patients in comparison to non-PKU individuals and nutritional deficiencies associated to the PKU diet are other important reasons to seek alternative therapies. In the last decade there has been an impressive effort in the investigation of other ways to treat PKU that might improve the outcome and quality of life of these patients. These studies have lead to the commercialization of sapropterin dihydrochloride, but there are still many questions regarding which patients to challenge with sapropterin what is the best challenge protocol and what could be the implications of this treatment in the long-term. Current human trials of PEGylated phenylalanine ammonia lyase are underway, which might render an alternative to diet for those patients non-responsive to sapropterin dihydrochloride. Preclinical investigation of gene and cell therapies for PKU is ongoing. In this manuscript, we will review the current knowledge on novel pharmacologic approaches to the treatment of phenylketonuria. PMID:21967857

  5. Prenatal diagnosis of Chinese families with phenylketonuria.

    PubMed

    Liu, N; Kong, X D; Zhao, D H; Wu, Q H; Li, X L; Guo, H F; Cui, L X; Jiang, M; Shi, H R

    2015-11-19

    The aim of this study is to investigate the ability to prenatally diagnose phenylketonuria (PKU) by using phenylalanine hydroxylase (PAH) gene mutation analysis combined with short tandem repeat (STR) linkage analysis in 118 fetuses from 112 Chinese families. Genomic DNA was extracted from the peripheral blood from members of 112 families and the exons and exon-intron boundaries of the PAH gene were amplified by PCR. PCR products were analyzed by bi-directional Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). The three variable number of tandem repeat (VNTR) markers PAH-1, PAH-26, PAH-32 were used in the prenatal diagnosis for the PKU families. We identified a spectrum of 63 different mutations, including 61 point mutations and indels, two large exon deletion mutations, and five novel mutations. A substantial proportion of mutant alleles were accounted for by p.R243Q (15.62%), EX6-96AG (9.82%), p.V399V (7.59%), p.Y356X (6.70%), and p.R413P (5.36%). The same mutations were identified in 31 prenatally genotyped fetuses. We identified 58 fetuses that carried only one mutant allele and 29 fetuses that carried no mutations of PAH and were presumed normal. PAH gene mutation analysis combined with STR linkage analysis can provide rapid and accurate prenatal diagnosis for PKU families.

  6. Phenylketonuria and the peoples of Northern Ireland.

    PubMed

    Zschocke, J; Mallory, J P; Eiken, H G; Nevin, N C

    1997-08-01

    The comparison of regional patterns of recessive disease mutations is a new source of information for studies of population genetics. The analysis of phenylketonuria (PKU) mutations in Northern Ireland shows that most major episodes of immigration have left a record in the modern genepool. The mutation 165T can be traced to the Palaeolithic people of western Europe who, in the Mesolithic period, first colonised Ireland. R408W (on haplotype 1) in contrast, the most common Irish PKU mutation, may have been prevalent in the Neolithic farmers who settled in Ireland after 4500 BC. No mutation was identified that could represent European Celtic populations, supporting the view that the adoption of Celtic culture and language in Ireland did not involve major migration from the continent. Several less common mutations can be traced to the Norwegian Atlantic coast and were probably introduced into Ireland by Vikings. This indicates that PKU has not been brought to Norway from the British Isles, as was previously argued. The rarity in Northern Ireland of IVS12nt1, the most common mutation in Denmark and England, indicates that the English colonialization of Ireland did not alter the local genepool in a direction that could be described as Anglo-Saxon. Our results show that the culture and language of a population can be independent of its genetic heritage, and give some insight into the history of the peoples of Northern Ireland.

  7. Protective Effect of Recombinant Adeno-Associated Virus 2/8-Mediated Gene Therapy from the Maternal Hyperphenylalaninemia in Offsprings of a Mouse Model of Phenylketonuria

    PubMed Central

    Park, Joo-Won; Oh, Hyun-Jeong; Choi, Jin-Ok; Seo, Kyung-In; Park, Eun-Sook; Park, Hae-Young

    2008-01-01

    Phenylketonuria (PKU) is an autosomal recessively inherited metabolic disorder caused by a deficiency of phenylalanine hydroxylase (PAH). The accumulation of phenylalanine leads to severe mental and psychomotor retardation, and the fetus of an uncontrolled pregnant female patient presents with maternal PKU syndrome. We have reported previously on the cognitive outcome of biochemical and phenotypic reversal of PKU in a mouse model, Pahenu2, by the AAV serotype 2-mediated gene delivery of a human PAH transgene. However, the therapeutic efficacy had been limited to only male PKU mice. In this study, we generated a pseudotyped recombinant AAV2/8-hPAH vector and infused it into female PKU mice through the hepatic portal vein or tail vein. Two weeks after injection, complete fur color change to black was observed in female PKU, as in males. The PAH activity in the liver increased to 65-70% of the wild-type activity in female PKU mice and to 90% in male PKU mice. Plasma phenylalanine concentration in female PKU mice decreased to the normal value. In addition, the offsprings of the treated female PKU mice can rescue from the harmful effect of maternal hyperphenylalaninemia. These results indicate that recombinant AAV2/8-mediated gene therapy is a potential therapeutic strategy for PKU. PMID:18955797

  8. Pretreatment cognitive and neural differences between sapropterin dihydrochloride responders and non-responders with phenylketonuria.

    PubMed

    Hawks, Zoë; Shimony, Joshua; Rutlin, Jerrel; Grange, Dorothy K; Christ, Shawn E; White, Desirée A

    2017-09-01

    Sapropterin dihydrochloride (BH4) reduces phenylalanine (Phe) levels and improves white matter integrity in a subset of individuals with phenylketonuria (PKU) known as "responders." Although prior research has identified biochemical and genotypic differences between BH4 responders and non-responders, cognitive and neural differences remain largely unexplored. To this end, we compared intelligence and white matter integrity prior to treatment with BH4 in 13 subsequent BH4 responders with PKU, 16 subsequent BH4 non-responders with PKU, and 12 healthy controls. Results indicated poorer intelligence and white matter integrity in non-responders compared to responders prior to treatment. In addition, poorer white matter integrity was associated with greater variability in Phe across the lifetime in non-responders but not in responders. These results underscore the importance of considering PKU as a multi-faceted, multi-dimensional disorder and point to the need for additional research to delineate characteristics that predict response to treatment with BH4.

  9. Epilepsy and phenylketonuria: a case description and EEG-fMRI findings.

    PubMed

    Guida, Melania; Pesaresi, Ilaria; Fabbri, Serena; Sartucci, Ferdinando; Cosottini, Mirco; Giorgi, Filippo Sean

    2014-01-01

    Phenylketonuria (PKU) is characterized by phenylalanine accumulation due to phenylalanine hydroxylase deficiency. Up to 50% of PKU patients experience seizures. We evaluated an adult PKU patient who suffered from absences and primarily generalized tonicclonic seizures, associated with generalized spikeand-wave discharges (GSWs) on EEG. An analysis of blood oxygenation level-dependent (BOLD) signal changes during interictal epileptiform discharges showed early activation of the left perirolandic cortex followed by a BOLD signal decrease within cortical regions belonging to the default mode network and left frontoparietal cortex. Moreover, deactivation of the head of the right caudate nucleus and the left thalamus was observed. The fMRI pattern observed in our patient during GSWs is similar but not identical to that observed in idiopathic generalized epilepsy, suggesting different neurophysiological mechanisms. This is the first description of BOLD-fMRI patterns in a PKU patient with epilepsy. Similar studies in more patients might help to uncover the pathophysiology of seizures in this disease.

  10. Modification of infant hypothyroidism and phenylketonuria screening program using electronic tools.

    PubMed

    Taheri, Behjat; Haddadpoor, Asefeh; Mirkhalafzadeh, Mahmood; Mazroei, Fariba; Aghdak, Pezhman; Nasri, Mehran; Bahrami, Gholamreza

    2017-01-01

    Congenital hypothyroidism and phenylketonuria (PKU) are the most common cause for preventable mental retardation in infants worldwide. Timely diagnosis and treatment of these disorders can have lasting effects on the mental development of newborns. However, there are several problems at different stages of screening programs that along with imposing heavy costs can reduce the precision of the screening, increasing the chance of undiagnosed cases which in turn can have damaging consequences for the society. Therefore, given these problems and the importance of information systems in facilitating the management and improving the quality of health care the aim of this study was to improve the screening process of hypothyroidism and PKU in infants with the help of electronic resources. The current study is a qualitative, action research designed to improve the quality of screening, services, performance, implementation effectiveness, and management of hypothyroidism and PKU screening program in Isfahan province. To this end, web-based software was designed. Programming was carried out using Delphi.net software and used SQL Server 2008 for database management. Given the weaknesses, problems, and limitations of hypothyroidism and PKU screening program, and the importance of these diseases in a national scale, this study resulted in design of hypothyroidism and PKU screening software for infants in Isfahan province. The inputs and outputs of the software were designed in three levels including Health Care Centers in charge of the screening program, provincial reference lab, and health and treatment network of Isfahan province. Immediate registration of sample data at the time and location of sampling, providing the provincial reference Laboratory and Health Centers of different eparchies with the ability to instantly observe, monitor, and follow-up on the samples at any moment, online verification of samples by reference lab, creating a daily schedule for reference lab

  11. Metabolomics of Dietary Fatty Acid Restriction in Patients with Phenylketonuria

    PubMed Central

    Mütze, Ulrike; Beblo, Skadi; Kortz, Linda; Matthies, Claudia; Koletzko, Berthold; Bruegel, Mathias; Rohde, Carmen; Thiery, Joachim; Kiess, Wieland; Ceglarek, Uta

    2012-01-01

    Background Patients with phenylketonuria (PKU) have to follow a lifelong phenylalanine restricted diet. This type of diet markedly reduces the intake of saturated and unsaturated fatty acids especially long chain polyunsaturated fatty acids (LC-PUFA). Long-chain saturated fatty acids are substrates of mitochondrial fatty acid oxidation for acetyl-CoA production. LC-PUFA are discussed to affect inflammatory and haemostaseological processes in health and disease. The influence of the long term PKU diet on fatty acid metabolism with a special focus on platelet eicosanoid metabolism has been investigated in the study presented here. Methodology/Principal Findings 12 children with PKU under good metabolic control and 8 healthy controls were included. Activated fatty acids (acylcarnitines C6–C18) in dried blood and the cholesterol metabolism in serum were analyzed by liquid chromatographic tandem mass spectrometry (LC-MS/MS). Fatty acid composition of plasma glycerophospholipids was determined by gas chromatography. LC-PUFA metabolites were analyzed in supernatants by LC-MS/MS before and after platelet activation and aggregation using a standardized protocol. Patients with PKU had significantly lower free carnitine and lower activated fatty acids in dried blood compared to controls. Phytosterols as marker of cholesterol (re-) absorption were not influenced by the dietary fatty acid restriction. Fatty acid composition in glycerophospholipids was comparable to that of healthy controls. However, patients with PKU showed significantly increased concentrations of y-linolenic acid (C18:3n-6) a precursor of arachidonic acid. In the PKU patients significantly higher platelet counts were observed. After activation with collagen platelet aggregation and thromboxane B2 and thromboxane B3 release did not differ from that of healthy controls. Conclusion/Significance Long-term dietary fatty acid restriction influenced the intermediates of mitochondrial beta-oxidation. No functional

  12. Specific prebiotics in a formula for infants with Phenylketonuria.

    PubMed

    MacDonald, Anita; Cochrane, Barbara; Wopereis, Harm; Loveridge, Nik

    2011-01-01

    This exploratory study investigated the influence of adding a patented, specific mixture of prebiotic oligosaccharides (scGOS/lcFOS [9:1 ratio], Danone Research) to a protein substitute suitable for infants with Phenylketonuria (PKU); PKU Anamix Infant (Nutricia). This was an 8-week open-label, single-arm, pilot intervention study in 9 infants (8-week median age) diagnosed with PKU. On study entry, infants were prescribed PKU Anamix Infant to replace an infant phenylalanine-free protein substitute without prebiotics (IPS). Blood phenylalanine concentrations were monitored and stool samples analyzed for pH/bacterial groups. PKU Anamix infant was well tolerated and accepted with no adverse events reported. Overall, plasma phenylalanine and tyrosine concentrations were maintained within target ranges throughout the study (120-360 μmol/l phenylalanine, 30-100 μmol/l tyrosine). All infants exhibited microbiota dominated by bifidobacteria (median 58.97% at Week 8), although no statistically significant change from baseline was observed at study endpoint. No infants showed abnormally high levels of Clostridium histolyticum/lituseburense or potentially pathogenic enterobacteriaceae at any point during the study. A significant reduction in median stool pH versus baseline was observed at Week 4 (pH reduced from 6.79 to 5.83), but this significance was not present at Week 8 (pH = 6.61). PKU Anamix Infant maintains phenylalanine control in line with established IPS without prebiotics and maintains levels of bifidobacteria and lowers stool pH. In exclusively breast-fed infants the latter two factors have been associated with a reduced risk of infection and may be of particular importance in infants with PKU. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Optimal serum phenylalanine for adult patients with phenylketonuria.

    PubMed

    Okano, Yoshiyuki; Nagasaka, Hironori

    2013-12-01

    High serum phenylalanine in adult patients with phenylketonuria (PKU) causes neuropsychological and psychosocial problems that can be resolved by phenylalanine-restricted diet. Therefore, PKU patients must continue to adhere to phenylalanine-restricted diet for life, although the optimal serum phenylalanine level in later life has yet to be established. The purpose of this review was to establish the optimal serum phenylalanine level in later life of PKU patients. We evaluated oxidative stress status, nitric oxide metabolism, cholesterol-derived oxysterols, vitamin D and bone status, and magnetic resonance imaging (MRI) in adult PKU patients according to serum phenylalanine level. Oxidative stress increased markedly at serum phenylalanine of 700-800 μmol/L. Serum phenylalanine higher than 700-850 μmol/L correlated with the disturbance of nitric oxide regulatory system. Adult PKU patients had poor vitamin D status and exhibited predominance of bone resorption over bone formation. In the brain, the levels of 24S-hydroxycholesterol, a marker of brain cholesterol elimination, were low at serum phenylalanine levels exceeding 650 μmol/L. MRI studies showed high signal intensity in deep white matter on T2-weighted and FLAIR images of PKU patients with serum phenylalanine greater than 500 μmol/L, with decreased apparent diffusion coefficients. Changes in most parameters covering the entire body organs in adult PKU were almost acceptable below 700-800 μmol/L of phenylalanine level. However, the optimal serum phenylalanine level should be 500 μmol/L or less in later life for the brain to be safe. © 2013.

  14. An Investigation of the Neurological and Neuropsychiatric Disturbances in Adults with Undiagnosed and/or Untreated Phenylketonuria in Poland

    ERIC Educational Resources Information Center

    Mazur, Artur; Jarochowicz, Sabina; Oltarzewski, Mariusz; Sykut-Cegielska, Jolanta; Gradowska, Wanda; Januszek-Trzciakowska, Aleksandra; O'Malley, Grace; Kwolek, Andrzej

    2011-01-01

    Background: The aim of the study was to determine neurological and neuropsychiatric manifestations in a group of patients with previously undiagnosed or untreated phenylketonuria (PKU) in the south-eastern part of Poland. Methods: The study was conducted among 400 adults with severe intellectual disability who were born prior to neonatal screening…

  15. An Investigation of the Neurological and Neuropsychiatric Disturbances in Adults with Undiagnosed and/or Untreated Phenylketonuria in Poland

    ERIC Educational Resources Information Center

    Mazur, Artur; Jarochowicz, Sabina; Oltarzewski, Mariusz; Sykut-Cegielska, Jolanta; Gradowska, Wanda; Januszek-Trzciakowska, Aleksandra; O'Malley, Grace; Kwolek, Andrzej

    2011-01-01

    Background: The aim of the study was to determine neurological and neuropsychiatric manifestations in a group of patients with previously undiagnosed or untreated phenylketonuria (PKU) in the south-eastern part of Poland. Methods: The study was conducted among 400 adults with severe intellectual disability who were born prior to neonatal screening…

  16. Mutation Spectrum of Six Genes in Chinese Phenylketonuria Patients Obtained through Next-Generation Sequencing

    PubMed Central

    Cen, Zhong; Yu, Li; Lin, Lin; Hao, Jing; Yang, Zhigang; Peng, Jiabao; Cui, Shujian; Huang, Jian

    2014-01-01

    Background The identification of gene variants plays an important role in the diagnosis of genetic diseases. Methodology/Principal Findings To develop a rapid method for the diagnosis of phenylketonuria (PKU) and tetrahydrobiopterin (BH4) deficiency, we designed a multiplex, PCR-based primer panel to amplify all the exons and flanking regions (50 bp average) of six PKU-associated genes (PAH, PTS, GCH1, QDPR, PCBD1 and GFRP). The Ion Torrent Personal Genome Machine (PGM) System was used to detect mutations in all the exons of these six genes. We tested 93 DNA samples from blood specimens from 35 patients and their parents (32 families) and 26 healthy adults. Using strict bioinformatic criteria, this sequencing data provided, on average, 99.14% coverage of the 39 exons at more than 70-fold mean depth of coverage. We found 23 previously documented variants in the PAH gene and six novel mutations in the PAH and PTS genes. A detailed analysis of the mutation spectrum of these patients is described in this study. Conclusions/Significance These results were confirmed by Sanger sequencing. In conclusion, benchtop next-generation sequencing technology can be used to detect mutations in monogenic diseases and can detect both point mutations and indels with high sensitivity, fidelity and throughput at a lower cost than conventional methods in clinical applications. PMID:24705691

  17. PKU and Maternal PKU: The Cure and the Problem.

    ERIC Educational Resources Information Center

    Henderson, Robert A.

    1989-01-01

    A longitudinal study is evaluating the efficacy of a phenylalanine-restricted diet in reducing disabling conditions associated with maternal hyperphenylalaninemia. Titled the Maternal PKU Collaborative Study, it is studying 162 American and Canadian women and involves diet therapy, prenatal examinations, laboratory tests, nutritional evaluation,…

  18. PKU and Maternal PKU: The Cure and the Problem.

    ERIC Educational Resources Information Center

    Henderson, Robert A.

    1989-01-01

    A longitudinal study is evaluating the efficacy of a phenylalanine-restricted diet in reducing disabling conditions associated with maternal hyperphenylalaninemia. Titled the Maternal PKU Collaborative Study, it is studying 162 American and Canadian women and involves diet therapy, prenatal examinations, laboratory tests, nutritional evaluation,…

  19. Nutrition education tools used in phenylketonuria: clinician, parent and patient perspectives from three international surveys.

    PubMed

    Bernstein, L E; Helm, J R; Rocha, J C; Almeida, M F; Feillet, F; Link, R M; Gizewska, M

    2014-04-01

    Three international surveys were developed aiming to identify the current nutrition educational tools used in the management of phenylketonuria (PKU) and the perceived effectiveness of these tools by clinicians, parents and patients. The first two surveys were distributed through the Metabolic Dietitians ListServe (pno-metabl@listserv.cc.emory.edu), and the third survey was distributed by international clinics and the National PKU Alliance website (www.npkua.org). A total of 888 responses (S1, n = 88; S2, n = 81; S3, n = 719) were collected from all three surveys. The surveys represent participants from 17 countries, in Europe; North America (USA and Canada); Mexico; Argentina; Turkey; Australia; and Africa (Tunisia). A consistent decline in 'parents as role models' as an educational tool was observed starting at age 10 years. Patients responded they feel their families are the most effective form of education, whereas handouts were selected as the least effective educational tool by patients. Parents responded they feel the most effective educational tool is one-on-one counselling. Patients and parents show a desirable trend in wanting to attend group clinic, even in centres where this type of educational tool is not offered. There was a discrepancy between clinicians and patient views regarding the perceived effectiveness of the nutrition education tools. Future research is needed surrounding the impact nutrition education may have on improved dietary compliance in patients with PKU. © 2013 The Authors Journal of Human Nutrition and Dietetics © 2013 The British Dietetic Association Ltd.

  20. Recommended Guidelines for PKU Programs.

    ERIC Educational Resources Information Center

    Children's Bureau (DHEW), Washington, DC.

    A discussion of screening tests for phenylketonuria recommends and provides some data on two tests, lists five disadvantages of urine tests, and discusses three new tests. Also considered are the role of the central laboratory facility and seven suggestions for screening different types of infants at different times. Treatment or followup programs…

  1. Intra-familiar discordant PKU phenotype explained by mutation analysis in three pedigrees.

    PubMed

    Trunzo, Roberta; Santacroce, Rosa; D'Andrea, Giovanna; Longo, Vittoria; De Girolamo, Giuseppe; Dimatteo, Claudia; Leccese, Angelica; Lillo, Vincenza; Papadia, Francesco; Margaglione, Maurizio

    2014-02-01

    Classical phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP) are two phenotypes of phenylalanine hydroxylase (PAH) deficiency with different degrees of severity. We have analyzed three families in which classical PKU, MHP and a normal phenotype occurred within each family due to the different combinations of three mutations segregating within the family. Indeed, sequence PAH analysis revealed three different alleles segregating in each family. This report suggests that when discordant phenotypes occur in a family, complete analysis of the PAH gene may be performed in order to support the diagnosis and assist in accurate genetic counseling and patient management. We further support the marked heterogeneity of hyperphenylalaninemia primarily due to allelic heterogeneity at the PAH locus. Copyright © 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  2. Adherence to tetrahydrobiopterin therapy in patients with phenylketonuria.

    PubMed

    Rohr, Frances; Wessel, Ann; Brown, Matthew; Charette, Kalin; Levy, Harvey L

    2015-01-01

    Phenylketonuria (PKU) is an inborn error in phenylalanine metabolism due to deficiency of the enzyme, phenylalanine hydroxylase (PAH). Treatment includes restriction of dietary phenylalanine, and in some individuals, supplementation with the PAH cofactor, tetrahydrobiopterin (sapropterin dihydrochloride). A survey was conducted among patients with PKU who had been prescribed sapropterin to assess reasons for continuing or discontinuing the drug. The primary reason that sapropterin responders discontinued the drug was because of side effects, followed by insufficient reduction of blood phenylalanine and insurance issues. Conversely, those who remained on therapy cited increased tolerance for dietary protein as the main reason for continuation, along with lower blood phenylalanine concentrations and feeling better. This study suggests that adherence to sapropterin therapy is mainly dependent upon the increase in dietary protein allowed when on the drug. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Mutational spectrum of phenylketonuria in Jiangsu province.

    PubMed

    Chen, Ya-fen; Jia, Hai-tao; Chen, Zhong-hai; Song, Jia-ping; Liang, Yu; Pei, Jing-jing; Wu, Zhi-jun; Wang, Jing; Qiu, Ya-li; Liu, Gang; Sun, Dong-mei; Jiang, Xin-ye

    2015-10-01

    Phenylketonuria (PKU) is caused by variants in the phenylalanine hydroxylase (PAH) gene. We systematically investigated all 13 exons of the PAH gene and their flanking introns in 31 unrelated patients and their parents using next-generation sequencing (NGS). A total of 33 different variants were identified in 58 of 62 mutant PAH alleles. The prevalent variants with a relative frequency of 5 % or more were c.721C > T, c.1068C > A, c.611A > G, c.1197A > T, c.728G > A, c.331C > T, and c.442-1G > A. One novel variant was identified in this study-c.699C > G. We studied genotype-phenotype correlations using the Guldberg arbitrary value (AV) system, which revealed a consistency rate of 38 % (8/21) among the 21 predicted phenotypes. The genotype-based prediction of BH4 responsiveness was also evaluated, and 14 patients (45.2 %) were predicted to be BH4 responsive. This study presents the spectrum of PAH variants in Jiangsu province. The information obtained from the genotype-based prediction of BH4 responsiveness might be used for the rational selection of candidates for BH4 testing. • Phenylketonuria (PKU) is caused by variants in the phenylalanine hydroxylase (PAH) gene. • The spectrum of PAH variants in different Chinese populations has been reported. What is new: • This is the first report on the spectrum of PAH variants in Jiangsu province. • This study identified one novel PAH variant-c.699C>G-and and tries to show a genotype-phenotype relationship also regarding BH4-responsiveness.

  4. Asymmetric dimethylarginine in children with homocystinuria or phenylketonuria.

    PubMed

    Kanzelmeyer, Nele; Tsikas, Dimitrios; Chobanyan-Jürgens, Kristine; Beckmann, Bibiana; Vaske, Bernhard; Illsinger, Sabine; Das, Anibh M; Lücke, Thomas

    2012-05-01

    Plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis from L-arginine and a cardiovascular risk factor, was found to be elevated in plasma of homocysteinemic adults. Enhanced cardiovascular risk due to homocystinuria and impaired renal function has been found in patients with phenylketonuria (PKU) on protein-restricted diet. However, it is still unknown whether ADMA synthesis is also elevated in children with homocystinuria due to cystathionine beta-synthase deficiency (classical homocystinuria), and whether ADMA may play a role in phenylketonuria in childhood. In the present study, we investigated the status of the L-arginine/NO pathway in six young patients with homocystinuria, in 52 young phenylketonuria patients on natural protein-restricted diet, and in age- and gender-matched healthy children serving as controls. ADMA in plasma and urine was determined by GC-MS/MS. The NO metabolites nitrate and nitrite in plasma and urine, and urinary dimethylamine (DMA), the dimethylarginine dimethylaminohydrolase (DDAH) metabolite of ADMA, were measured by GC-MS. Unlike urine ADMA excretion, plasma ADMA concentration in patients with homocystinuria was significantly higher than in controls (660±158 vs. 475±77 nM, P=0.035). DMA excretion rate was considerably higher in children with homocystinuria as compared to controls (62.2±24.5 vs. 6.5±2.9 μmol/mmol creatinine, P=0.068), indicating enhanced DDAH activity in this disease. In contrast and unexpectedly, phenylketonuria patients had significantly lower ADMA plasma concentrations compared to controls (512±136 vs. 585±125 nM, P=0.009). Phenylketonuria patients and controls had similar L-arginine/ADMA molar ratios in plasma. Urinary nitrite excretion was significantly higher in phenylketonuria as compared to healthy controls (1.7±1.7 vs. 0.7±1.2 μmol/mmol creatinine, P=0.003). Our study shows that the L-arginine/NO pathway is differently altered in children

  5. Food Products Made With Glycomacropeptide, a Low Phenylalanine Whey Protein, Provide a New Alternative to Amino Acid-Based Medical Foods for Nutrition Management of Phenylketonuria

    PubMed Central

    Van Calcar, Sandra C.; Ney, Denise M.

    2012-01-01

    Phenylketonuria (PKU), an inborn error in phenylalanine (phe) metabolism, requires lifelong nutrition management with a low-phe diet, which includes a phe-free amino acid-based medical formula to provide the majority of an individual’s protein needs. Compliance with this diet is often difficult for older children, adolescents and adults with PKU. The whey protein glycomacropeptide (GMP) is ideally suited for the PKU diet since it is naturally low in phe. Nutritionally complete, acceptable medical foods and beverages can be made with GMP to increase the variety of protein sources for the PKU diet. As an intact protein, GMP improves protein utilization and increases satiety compared with amino acids. Thus, GMP provides a new, more physiologic source of low-phe dietary protein for those with PKU. PMID:22818728

  6. Bone Impairment in Phenylketonuria Is Characterized by Circulating Osteoclast Precursors and Activated T Cell Increase

    PubMed Central

    Mussa, Alessandro; D'Amico, Lucia; Fiore, Ludovica; Garelli, Davide; Spada, Marco; Ferracini, Riccardo

    2010-01-01

    Background Phenylketonuria (PKU) is a rare inborn error of metabolism often complicated by a progressive bone impairment of uncertain etiology, as documented by both ionizing and non- ionizing techniques. Methodology Peripheral blood mononuclear cell (PBMC) cultures were performed to study osteoclastogenesis, in the presence or absence of recombinant human monocyte-colony stimulating factor (M-CSF) and receptor activator of NFκB ligand (RANKL). Flow cytometry was utilized to analyze osteoclast precursors (OCPs) and T cell phenotype. Tumour necrosis factor α (TNF-α), RANKL and osteoprotegerin (OPG) were quantified in cell culture supernatants by ELISA. The effects of RANKFc and anti-TNF-α antibodies were also investigated to determine their ability to inhibit osteoclastogenesis. In addition, bone conditions and phenylalanine levels in PKU patients were clinically evaluated. Principal Findings Several in vitro studies in PKU patients' cells identified a potential mechanism of bone formation inhibition commonly associated with this disorder. First, PKU patients disclosed an increased osteoclastogenesis compared to healthy controls, both in unstimulated and M-CSF/RANKL stimulated PBMC cultures. OCPs and the measured RANKL/OPG ratio were higher in PKU patients compared to healthy controls. The addition of specific antagonist RANKFc caused osteoclastogenesis inhibition, whereas anti-TNF-α failed to have this effect. Among PBMCs isolated from PKU patients, activated T cells, expressing CD69, CD25 and RANKL were identified. Confirmatory in vivo studies support this proposed model. These in vivo studies included the analysis of osteoclastogenesis in PKU patients, which demonstrated an inverse relation to bone condition assessed by phalangeal Quantitative Ultrasound (QUS). This was also directly related to non-compliance to therapeutic diet reflected by hyperphenylalaninemia. Conclusions Our results indicate that PKU spontaneous osteoclastogenesis depends on the

  7. Relationships between lumbar bone mineral density and biochemical parameters in phenylketonuria patients.

    PubMed

    de Groot, Martijn J; Hoeksma, Marieke; van Rijn, Margreet; Slart, Riemer H J A; van Spronsen, Francjan J

    2012-04-01

    The etiology of reduced bone mineral density (BMD) in phenylketonuria (PKU) is unknown. Reduced BMD may be inherent to PKU and/or secondary to its dietary treatment. Lumbar BMD was measured by dual-energy X-ray absorptiometry in 53 early and continuously treated PKU patients (median age 16, range 2-35 years). First, Z-scores of BMD were correlated to age group, clinical severity of PKU, mean phenylalanine (Phe) concentration and Phe variation in the year prior to DXA scanning, as well as to blood vitamin, mineral, and alkaline phosphatase concentrations. Second, parameters were compared between subjects with reduced BMD (Z-score<-2 SD) and subjects with normal BMD. BMD was significantly reduced in our cohort (p=0.000). Z-scores of BMD were neither significantly correlated to age group, nor clinical severity of PKU. Both mean Phe concentration and Phe variation in the year prior to DXA scanning did not significantly correlate with Z-scores of BMD. Higher blood calcium concentrations were significantly associated with lower BMD (r(2)=-0.485, p=0.004). Other biochemical parameters, including vitamin B12 availability markers, did not show significant correlations with Z-score of BMD. Subjects with reduced BMD had significantly higher blood phosphorus concentrations than subjects with normal BMD (p=0.009). No other significant differences were found between both BMD groups. Reduced BMD in PKU is present from early age onward and does not progress with age. Therefore, BMD deserves attention from early age onward in PKU patients. Our findings are consistent with increased bone turnover in PKU. It remains unclear whether reduced BMD is inherent to PKU and/or secondary to its dietary treatment. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Phenylketonuria: Direct and indirect effects of phenylalanine.

    PubMed

    Schlegel, Gudrun; Scholz, Ralf; Ullrich, Kurt; Santer, René; Rune, Gabriele M

    2016-07-01

    High phenylalanine concentrations in the brain due to dysfunctional phenylalanine hydroxylase (Pah) are considered to account for mental retardation in phenylketonuria (PKU). In this study, we treated hippocampal cultures with the amino acid in order to determine the role of elevated levels of phenylalanine in PKU-related mental retardation. Synapse density and dendritic length were dramatically reduced in hippocampal cultures treated with phenylalanine. Changes in cofilin expression and phosphorylation status, which were restored by NMDA, as well as reduced activation of the small GTPase Rac1, likely underlie these structural alterations. In the Pah(enu2) mouse, which carries a mutated Pah gene, we previously found higher synaptic density due to delayed synaptic pruning in response to insufficient microglia function. Microglia activity and C3 complement expression, both of which were reduced in the Pah(enu2) mouse, however, were unaffected in hippocampal cultures treated with phenylalanine. The lack of a direct effect of phenylalanine on microglia is the key to the opposite effects regarding synapse stability in vitro and in the Pah(enu2) mouse. Judging from our data, it appears that another player is required for the inactivation of microglia in the Pah(enu2) mouse, rather than high concentrations of phenylalanine alone. Altogether, the data underscore the necessity of a lifelong phenylalanine-restricted diet. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Comparison of Adeno-Associated Virus Pseudotype 1, 2, and 8 Vectors Administered by Intramuscular Injection in the Treatment of Murine Phenylketonuria

    PubMed Central

    Rebuffat, Alexandre; Harding, Cary O.; Ding, Zhaobing

    2010-01-01

    Abstract Phenylketonuria (PKU) is caused by hepatic phenylalanine hydroxylase (PAH) deficiency and is associated with systemic accumulation of phenylalanine (Phe). Previously we demonstrated correction of murine PKU after intravenous injection of a recombinant type 2 adeno-associated viral vector pseudotyped with type 8 capsid (rAAV2/8), which successfully directed hepatic transduction and Pah gene expression. Here, we report that liver PAH activity and phenylalanine clearance were also restored in PAH-deficient mice after simple intramuscular injection of either AAV2 pseudotype 1 (rAAV2/1) or rAAV2/8 vectors. Serotype 2 AAV vector (rAAV2/2) was also investigated, but long-term phenylalanine clearance has been observed only for pseudotypes 1 and 8. Therapeutic correction was shown in both male and female mice, albeit more effectively in males, in which correction lasted for the entire period of the experiment (>1 year). Although phenylalanine levels began to rise in female mice at about 8–10 months after rAAV2/8 injection they remained only mildly hyperphenylalaninemic thereafter and subsequent supplementation with synthetic tetrahydrobiopterin resulted in a transient decrease in blood phenylalanine. Alternatively, subsequent administration of a second vector with a different AAV pseudotype to avoid immunity against the previously administrated vector was also successful for long-term treatment of female PKU mice. Overall, this relatively less invasive gene transfer approach completes our previous studies and allows comparison of complementary strategies in the development of efficient PKU gene therapy protocols. PMID:19916803

  10. Controlled diet in phenylketonuria and hyperphenylalaninemia may cause serum selenium deficiency in adult patients: the Czech experience.

    PubMed

    Procházková, Dagmar; Jarkovský, Jiří; Vinohradská, Hana; Konečná, Petra; Machačová, Lucie; Doležel, Zdeněk

    2013-08-01

    Phenylketonuria is an inherited disorder of metabolism of the amino acid phenylalanine caused by a deficit of the enzyme phenylalanine hydroxylase. It is treated with a low-protein diet containing a low content of phenylalanine to prevent mental affection of the patient. Because of the restricted intake of high-biologic-value protein, patients with phenylketonuria may have lower than normal serum concentrations of pre-albumin, selenium, zinc and iron. The objective of the present study was to assess the compliance of our phenylketonuric (PKU) and hyperphenylalaninemic (HPA) patients; to determine the concentration of serum pre-albumin, selenium, zinc and iron to discover the potential correlation between the amount of proteins in food and their metabolic control. We studied 174 patients of which 113 were children (age 1-18), 60 with PKU and 53 with HPA and 61 were adults (age 18-42), 51 with PKU and 10 with HPA. We did not prove a statistically significant difference in the concentration of serum pre-albumin, zinc and iron among the respective groups. We proved statistically significant difference in serum selenium concentrations of adult PKU and HPA patients (p = 0.006; Mann-Whitney U test). These results suggest that controlled low-protein diet in phenylketonuria and hyperphenylalaninemia may cause serum selenium deficiency in adult patients.

  11. Alternative therapies to address the unmet medical needs of patients with phenylketonuria.

    PubMed

    Blau, Nenad; Longo, Nicola

    2015-04-01

    Standard therapy for phenylketonuria (PKU), the most common inherited disorder in amino acid metabolism, is an onerous phenylalanine-restricted diet. Adherence to this stringent diet regimen decreases as patients get older, and this lack of adherence is directly associated with cognitive and executive dysfunction and psychiatric issues. These factors emphasize the need for alternative pharmacological therapies to help treat patients with PKU. Sapropterin dihydrochloride is a synthetic form of tetrahydrobiopterin, the cofactor of phenylalanine hydroxylase that in pharmacological doses can stabilize and increase residual enzyme activity in some patients with PKU. About one-third of all patients with PKU respond to oral sapropterin. Phenylalanine ammonia lyase (PAL) is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. Phase I and II trials have shown that injectable recombinant Anabaena variabilis PAL produced in Escherichia coli conjugated with PEG can reduce phenylalanine levels in subjects with PKU. The most frequently reported adverse events were injection-site reactions, dizziness and immune reactions. Additionally, oral administration of PAL and delivery of enzyme substitution therapies by encapsulation in erythrocytes are being investigated. Novel therapies for patients with PKU appear to be options to reduce phenylalanine levels, and may reduce the deleterious effects of this disorder.

  12. Diet in phenylketonuria: a snapshot of special dietary costs and reimbursement systems in 10 international centers.

    PubMed

    Belanger-Quintana, A; Dokoupil, K; Gokmen-Ozel, H; Lammardo, A M; MacDonald, A; Motzfeldt, K; Nowacka, M; Robert, M; van Rijn, M; Ahring, K

    2012-03-01

    To gather exploratory data on the costs and reimbursement of special dietary foods used in the management of phenylketonuria (PKU) from ten international specialist PKU centers. Experts from each center provided data on retail costs of the three most frequently used phenylalanine-free protein substitutes and low-protein foods at their center; reimbursement of protein substitutes and low-protein foods; and state monetary benefits provided to PKU patients. The mean annual cost of protein substitutes across 4 age groups (2 y, 8 y, 15 y and adults) ranged from €4273 to €21,590 per patient. The cost of low-protein products also differed; the mean cost of low-protein bread varied from €0.04 to €1.60 per 100 kcal. All protein substitutes were either fully reimbursed or covered by health insurance. However, reimbursement for low-protein products varied and state benefits differed between centers. The variation in the cost and reimbursement of diet therapy and the level of additional state benefits for PKU patients demonstrates the large difference in expenditure on and access to PKU dietary products. This highlights the inequality between healthcare systems and access to special dietary products for people with PKU, ultimately leading to patients in some countries receiving better care than others. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan.

    PubMed

    Okano, Yoshiyuki; Kudo, Satoshi; Nishi, Yasuaki; Sakaguchi, Tomoko; Aso, Kazuyoshi

    2011-04-01

    Phenylketonuria (PKU) is a heterogeneous metabolic disorder caused by a deficiency in hepatic phenylalanine hydroxylase (PAH). On the basis of phenotype/genotype correlations, determination of phenylketonuric genotype is important for classification of the clinical phenotype and treatment of PKU, including tetrahydrobiopterin therapy. We characterized the genotypes of 203 Japanese patients with PKU and hyperphenylalaninemia using the following systems: (1) denaturing high-performance liquid chromatography with a GC-clamped primer; (2) direct sequencing; and, (3) multiplex ligation-dependent probe amplification. Of 406 mutant alleles, 390 (96%) were genotyped; 65 mutations were identified, including 22 new mutations. R413P, R241C, IVS4-1g>a, R111X and R243Q were prevalent mutations. Mutations prevalent in the Japanese cohort are also common in Korean and Northern Chinese populations, suggesting same origin. The spectrum of prevalent mutations was not significantly different among six Japanese districts, indicating that Japan comprises a relatively homogeneous ethnic group. We classified the mutations by clinical phenotypes and in vivo PAH activity and estimated the mutations with potential tetrahydrobiopterin (BH(4)) responsiveness. The frequency of BH(4) responsiveness based on the genotype was 29.1% in Japanese PKU patients. A catalog of PKU genotypes would be useful for predicting clinical phenotype, deciding on the subsequent treatment of PKU including BH(4) therapy, and genetic counseling in East Asia.

  14. Longitudinal modelling of the exposure of young UK patients with PKU to acesulfame K and sucralose.

    PubMed

    O'Sullivan, Aaron J; Pigat, Sandrine; O'Mahony, Cian; Gibney, Michael J; McKevitt, Aideen I

    2017-08-23

    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. Young patients with PKU aged 1-3 years can be exposed to higher levels of artificial sweeteners from these dual sources than normal healthy children and are at a higher risk of exceeding the ADI. Standard intake assessment methods are not adequate to assess the additive exposure of young patients with PKU. The aim of this study was to estimate the combination effect on the intake of artificial sweeteners and the impact of the introduction of new provisions for an artificial sweetener (sucralose, E955) on exposure of PKU patients using a validated probabilistic model. Food consumption data were derived from the food consumption survey data of healthy young children in the United Kingdom from the National Diet and Nutrition Survey (NDNS, 1992-2012). Specially formulated protein substitutes as foods for special medical purposes (FSMPs) were included in the exposure model to replace restricted foods. Inclusion of these protein substitutes is based on recommendations to ensure adequate protein intake in these patients. Exposure assessment results indicated the availability of sucralose for use in FSMPs for PKU leads to changes in intakes in young patients. These data further support the viability of probabilistic modelling as a means to estimate food additive exposure in patients consuming medical nutrition products.

  15. [Cost/benefit study of the neonatal detection of phenylketonuria and hypothyroidism].

    PubMed

    Dhondt, J L; Farriaux, J P; Lebrun, T; Sailly, J C

    1988-01-01

    The medical importance of an early screening for phenylketonuria (PKU) and congenital hypothyroidism (CH) has been recognized for a long time. However, only rare cost-benefit analysis have been reported. A comparison between the cost of identification and care of PKU and CH patients and the expenditure for the care of untreated retarded patients has been established on the basis of the activity of the Nord-Pas-de-Calais regional screening centre and of patient's families interviews. The present analysis yields a cost-benefit ratio of 6.5 for PKU and 12.2 for CH prophylaxis. However cost-benefit varies depending on the economical partner: patient's family, Social Security or Administration. The present model may also be useful cost-benefit calculation when new tests will be planned to be introduced in the national neonatal screening programme.

  16. Systematic Review and Meta-Analysis of Neuropsychiatric Symptoms and Executive Functioning in Adults With Phenylketonuria

    PubMed Central

    Bilder, Deborah A.; Noel, J. Kay; Baker, Erin R.; Irish, William; Chen, Yinpu; Merilainen, Markus J.; Prasad, Suyash; Winslow, Barbara J.

    2016-01-01

    ABSTRACT This systematic review and meta-analysis (MA) investigates the impact of elevated blood phenylalanine (Phe) on neuropsychiatric symptoms in adults with phenylketonuria (PKU). The meta-analysis of PKU is challenging because high-quality evidence is lacking due to the limited number of affected individuals and few placebo-controlled, double-blind studies of adults with high and low blood Phe. Neuropsychiatric symptoms associated with PKU exceed general population estimates for inattention, hyperactivity, depression, and anxiety. High Phe is associated with an increased prevalence of neuropsychiatric symptoms and executive functioning deficits whereas low Phe is associated with improved neurological performance. Findings support lifelong maintenance of low blood Phe. PMID:27805419

  17. Mutation analysis of PAH gene and characterization of a recurrent deletion mutation in Korean patients with phenylketonuria

    PubMed Central

    Lee, Yong-Wha; Lee, Dong Hwan; Kim, Nam-Doo; Lee, Seung-Tae; Ahn, Jee Young; Choi, Tae-Youn; Lee, You Kyoung; Kim, Sun-Hee; Kim, Jong-Won

    2008-01-01

    Phenylketonuria (PKU; MIM 261600) is an autosomal recessive metabolic disorder caused by a deficiency of phenylalanine hydroxylase (PAH; EC 1.14.16.1). Point mutations in the PAH gene are known to cause PKU in various ethnic groups, and large deletions or duplications account for up to 3% of the PAH mutations in some ethnic groups. However, a previous study could not identify ~14% of the mutant alleles by sequence analysis in Korean patients with PKU, which suggests that large deletions or duplication might be frequent causes of PKU in Koreans. To test this hypothesis, we performed multiplex ligation-dependent probe amplification (MLPA) for the identification of uncharacterized mutant alleles after PAH sequence analysis of 33 unrelated Korean patients with PKU. Bi-directional sequencing of the PAH exons and flanking intronic regions revealed 27 different mutations, including four novel mutations (two missense and two deletion mutations), comprising 57/66 (86%) mutant alleles. MLPA identified a large deletion that encompassed exons 5 and 6 in four patients, another large deletion that extended from exon 4 to exon 7 in one patient, and a duplication of exon 4 in one patient. Chromosomal walking characterized the deletion breakpoint of the most common large deletion that involved exons 5 and 6 (c.456_706+138del). The present study shows that the allelic frequency of exon deletion or duplication is 9% (6/66) in Korean PKU patients, which suggests that these mutations may be frequent causes of PKU in Korean subjects. PMID:18985011

  18. Phenylketonuria: a 21st century perspective.

    PubMed

    van Spronsen, Francjan J

    2010-09-01

    Phenylketonuria is the most prevalent inherited defect in amino acid metabolism. Owing to mutations in the gene encoding the enzyme phenylalanine hydroxylase, the essential amino acid phenylalanine cannot be hydroxylated to tyrosine and blood and tissue concentrations of phenylalanine increase. Untreated, phenylketonuria causes severe mental retardation, epilepsy and behavioral problems. The combined effect of neonatal screening and treatment has, however, meant that phenylketonuria is now a biochemical rather than a clinical diagnosis. Treatment consists of stringent dietary restriction of natural protein intake and supplementation of amino acids other than phenylalanine by a chemically manufactured protein substitute. Although clinical outcome on a phenylalanine-restricted diet is good, neuropsychological deficits are now known to exist in dietary-treated patients with phenylketonuria, and quality of life, nutritional condition and psychosocial outcome could probably also be improved. The need for new therapeutic approaches is being met by supplementation with tetrahydrobiopterin or large neutral amino acids, whilst development of the use of phenylalanine ammonia lyase, and, in the longer term, gene therapy and chaperone treatment holds promise. This Review provides an overview of the history of phenylketonuria, the challenges of treatment today and the treatment possibilities in the near future.

  19. Phenylketonuria: a review of current and future treatments

    PubMed Central

    Al Hafid, Naz

    2015-01-01

    Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism caused by a deficiency in the hepatic enzyme phenylalanine hydroxylase (PAH). If left untreated, the main clinical feature is intellectual disability. Treatment, which includes a low Phe diet supplemented with amino acid formulas, commences soon after diagnosis within the first weeks of life. Although dietary treatment has been successful in preventing intellectual disability in early treated PKU patients, there are major issues with dietary compliance due to palatability of the diet. Other potential issues associated with dietary therapy include nutritional deficiencies especially vitamin D and B12. Suboptimal outcomes in cognitive and executive functioning have been reported in patients who adhere poorly to dietary therapy. There have been continuous attempts at improving the quality of medical foods including their palatability. Advances in dietary therapy such as the use of large neutral amino acids (LNAA) and glycomacropeptides (GMP; found within the whey fraction of bovine milk) have been explored. Gene therapy and enzyme replacement or substitution therapy have yielded more promising data in the recent years. In this review the current and possible future treatments for PKU are discussed. PMID:26835392

  20. Rapid screening of phenylketonuria using a CD microfluidic device.

    PubMed

    Chen, Bin; Zhou, Xiaomian; Li, Chunyu; Wang, Qiuping; Liu, Dayu; Lin, Bingcheng

    2011-04-08

    We herein present a compact disc (CD) microfluidic chip based hybridization assay for phenylketonuria (PKU) screening. This CD chip is composed of a polydimethylsiloxane (PDMS) top layer containing 12 DNA hybridization microchannels, and a glass bottom layer with hydrogel pad conjugated DNA oligonucleotides. Reciprocating flow was generated on the CD chip through a simple rotation-pause operation to facilitate rapid DNA hybridization. When rotated the CD chip, the sample solution was driven into the hybridization channel by centrifugal force. When stopped the CD chip, the sample plug was pulled backward through the channel by capillary force. The hybridization assay was firstly validated with control samples and was then used to analyze 30 clinical samples from pregnant women with suspected PKU fetus. The on-chip DNA hybridization was completed in 15 min with a sample consumption as low as 1.5μL, and the limit-of-detection (LOD) of DNA template was 0.7ng/μL. Among the 30 samples tested, V245V mutation was identified in 4 cases while R243Q mutation was detected in one case. Results of the hybridization assay were confirmed by DNA sequencing. This CD-chip based hybridization assay features short analysis time, simple operation and low cost, thus has the potential to serve as the tool for PKU screening.

  1. Does a lower carbohydrate protein substitute impact on blood phenylalanine control, growth and appetite in children with PKU?

    PubMed

    Gokmen-Ozel, Hulya; Ferguson, Carol; Evans, Sharon; Daly, Anne; MacDonald, Anita

    2011-01-01

    In children with phenylketonuria (PKU), it is possible that high carbohydrate protein substitutes may adversely affect blood phenylalanine control. We evaluated if a low carbohydrate, 'ready-to-drink' protein substitute would impact on short term blood phenylalanine control, weight and appetite in children with PKU aged 3-10 years. This was a 3-part, 5-week randomised, controlled, crossover study in which two different carbohydrate/protein-equivalent ratios in protein substitute [control protein substitute (CPS) median 1:1; trial protein substitute (TPS) 0.5:1] were compared. The effects on feeding behaviour, weight change and phenylalanine concentrations were studied. Fourteen children (12 boys; median age 6.3 y, range 3 to 9.7 y) with PKU on diet were recruited from 2 treatment centres. Phenylalanine control did not deteriorate with TPS and remained unchanged between pre-study and CPS (p = 0.783). No statistical differences were noted in energy intake between the two study parts. Any changes in weight were similar between the two groups and there was limited change in feeding behaviour. This study suggests that the carbohydrate/protein-equivalent ratio of protein substitutes can be reduced to 0.5:1 with no loss of blood phenylalanine control or adverse effect on weight gain in children with PKU. Copyright © 2011 Elsevier Inc. All rights reserved.

  2. Long-term treatment of phenylketonuria with a new medical food containing large neutral amino acids

    PubMed Central

    Concolino, D; Mascaro, I; Moricca, M T; Bonapace, G; Matalon, K; Trapasso, J; Radhakrishnan, G; Ferrara, C; Matalon, R; Strisciuglio, P

    2017-01-01

    Background/Objectives: Phenylketonuria (PKU) is an autosomal recessive disease caused by deficient activity of phenylalanine hydroxylase. A low phenylalanine (Phe) diet is used to treat PKU. The diet is very restrictive, and dietary adherence tends to decrease as patients get older. Methods to improve dietary adherence and blood Phe control are continuously under investigation. Subjects/Methods: A new formula Phe-neutral amino acid (PheLNAA) has been tested in this study with the purpose of improving the compliance and lowering blood phenylalanine. The formula has been tested for nitrogen balance, and it is nutritionally complete. It is fortified with more nutritional additives that can be deficient in the PKU diet, such as B12, Biotin, DHA, Lutein and increased levels of large neutral amino acids to help lower blood Phe. The new formula has been tested on 12 patients with a loading test of 4 weeks. Results: Fifty-eight percent of patients had a significant decline in blood Phe concentration from baseline throughout the study. The PheLNAA was well tolerated with excellent compliance and without illnesses during the study. Conclusions: In conclusion, the new formula is suitable for life-long treatment of PKU, and it offers the PKU clinic a new choice for treatment. PMID:27623981

  3. Phenylketonuria and Gut Microbiota: A Controlled Study Based on Next-Generation Sequencing

    PubMed Central

    Pinheiro de Oliveira, Felipe; Mendes, Roberta Hack; Dobbler, Priscila Thiago; Mai, Volker; Pylro, Victor Salter; Waugh, Sheldon G; Vairo, Filippo; Refosco, Lilia Farret; Schwartz, Ida Vanessa Doederlein

    2016-01-01

    Phenylketonuria (PKU) is an inborn error of metabolism associated with high blood levels of phenylalanine (Phe). A Phe-restricted diet supplemented with L-amino acids is the main treatment strategy for this disease; if started early, most neurological abnormalities can be prevented. The healthy human gut contains trillions of commensal bacteria, often referred to as the gut microbiota. The composition of the gut microbiota is known to be modulated by environmental factors, including diet. In this study, we compared the gut microbiota of 8 PKU patients on Phe-restricted dietary treatment with that of 10 healthy individuals. The microbiota were characterized by 16S rRNA sequencing using the Ion Torrent™ platform. The most dominant phyla detected in both groups were Bacteroidetes and Firmicutes. PKU patients showed reduced abundance of the Clostridiaceae, Erysipelotrichaceae, and Lachnospiraceae families, Clostridiales class, Coprococcus, Dorea, Lachnospira, Odoribacter, Ruminococcus and Veillonella genera, and enrichment of Prevotella, Akkermansia, and Peptostreptococcaceae. Microbial function prediction suggested significant differences in starch/glucose and amino acid metabolism between PKU patients and controls. Together, our results suggest the presence of distinct taxonomic groups within the gut microbiome of PKU patients, which may be modulated by their plasma Phe concentration. Whether our findings represent an effect of the disease itself, or a consequence of the modified diet is unclear. PMID:27336782

  4. Gypsy Phenylketonuria: A point mutation of the phenylalanine hydroxylase gene in Gypsy families from Slovakia

    SciTech Connect

    Kalanin, J.; Takarada, Y.; Kagawa, S.; Yamashita, K.; Ohtsuka, N.; Matsuoka, A.

    1994-01-15

    A direct mutational analysis of the phenylalanine hydroxylase gene (PAH) in Gypsy families with phenylketonuria (PKU) has not yet been presented. However, they obviously represent a group at high risk for this inherited disease. The authors analyzed the PAH loci of 65 Gypsies originating from Eastern Slovakia by a combination of PCR amplification, direct sequencing and ASO hybridization. These studies uncovered 10 {open_quotes}classical PKU{close_quotes} patients to be homozygous for a R252W (CGG-TGG) transition, and 29 heterozygous carriers of this mutation. Fifteen control Caucasoid PKU patients from the Czech and Slovak Republics were selected. In this group they detected R252W mutation in two subjects (6.67% of all mutant alleles). Both were compound heterozygous for two different mutations. Previous haplotype studies of Welsh Gypsies with PKU were uninformative in the determination of heterozygosity. ASO hybridization served effectively for the consequent analyses in Gypsy PKU-related families and to identify the carriers among the unrelated subjects. 19 refs., 2 figs.

  5. Long-term treatment for hyperphenylalaninemia and phenylketonuria: a risk for nutritional vitamin B12 deficiency?

    PubMed

    Procházková, Dagmar; Jarkovský, Jiří; Haňková, Zdena; Konečná, Petra; Benáková, Hana; Vinohradská, Hana; Mikušková, Alena

    2015-11-01

    The objective of the study was to determine the incidence of vitamin B12 deficiency in patients under long-term treatment for phenylketonuria (PKU) and hyperphenylalaninemia (HPA), as well as its associations with B12 vitamin parameters (holotranscobalamin - active vitamin B12, serum folate, total plasma homocysteine, and plasma methylmalonic acid concentration). The group consisted of 51 PKU (n=29) and HPA (n=22) patients aged 3-48 years (28 children, 23 adults). A significant difference in serum folate levels was discovered between adult HPA patients and PKU patients (p=0.004, Mann-Whitney U-test). A significant difference in plasma homocysteine concentrations within the normal levels (p=0.032, χ2-test) was detected between adult HPA and PKU patients. In the group of adults, we also found significant differences in serum holotranscobalamin concentrations regarding both concentration levels and the proportion of patients with concentrations within the normal levels (p=0.031, Mann-Whitney U-test; p=0.006, χ2-test). We have proven that adult patients with PKU and HPA are at risk of vitamin B12 nutritional deficiency. The most effective parameter for these adults is the monitoring of holotranscobalamin in the serum.

  6. Phenylketonuria and Gut Microbiota: A Controlled Study Based on Next-Generation Sequencing.

    PubMed

    Pinheiro de Oliveira, Felipe; Mendes, Roberta Hack; Dobbler, Priscila Thiago; Mai, Volker; Pylro, Victor Salter; Waugh, Sheldon G; Vairo, Filippo; Refosco, Lilia Farret; Roesch, Luiz Fernando Würdig; Schwartz, Ida Vanessa Doederlein

    2016-01-01

    Phenylketonuria (PKU) is an inborn error of metabolism associated with high blood levels of phenylalanine (Phe). A Phe-restricted diet supplemented with L-amino acids is the main treatment strategy for this disease; if started early, most neurological abnormalities can be prevented. The healthy human gut contains trillions of commensal bacteria, often referred to as the gut microbiota. The composition of the gut microbiota is known to be modulated by environmental factors, including diet. In this study, we compared the gut microbiota of 8 PKU patients on Phe-restricted dietary treatment with that of 10 healthy individuals. The microbiota were characterized by 16S rRNA sequencing using the Ion Torrent™ platform. The most dominant phyla detected in both groups were Bacteroidetes and Firmicutes. PKU patients showed reduced abundance of the Clostridiaceae, Erysipelotrichaceae, and Lachnospiraceae families, Clostridiales class, Coprococcus, Dorea, Lachnospira, Odoribacter, Ruminococcus and Veillonella genera, and enrichment of Prevotella, Akkermansia, and Peptostreptococcaceae. Microbial function prediction suggested significant differences in starch/glucose and amino acid metabolism between PKU patients and controls. Together, our results suggest the presence of distinct taxonomic groups within the gut microbiome of PKU patients, which may be modulated by their plasma Phe concentration. Whether our findings represent an effect of the disease itself, or a consequence of the modified diet is unclear.

  7. Household financial burden of phenylketonuria and its impact on treatment in China: a cross-sectional study.

    PubMed

    Wang, Lin; Zou, Hui; Ye, Fang; Wang, Kundi; Li, Xiaowen; Chen, Zhihua; Chen, Jie; Han, Bingjuan; Yu, Weimin; He, Chun; Shen, Ming

    2017-05-01

    Phenylketonuria (PKU) is a rare inborn disease, which, untreated, leading to severe neurobehavioral dysfunction. Considering its complexity, the management of PKU may bring a formidable economic burden to parents and caregivers. It is still unknown what the out-of-pocket expenses are for a patient with PKU in China. This paper explores the household financial burden of classical PKU and its impact on Chinese families in a quantitative manner for the first time. A non-interventional and observational study was conducted at the China-Japan Friendship Hospital, one of the national centers for inherited metabolic disorders in China. The medical and non-medical household financial burdens were consolidated into a questionnaire to evaluate the out-of-pocket costs (OOPCs) of PKU treatment and follow-up. The total OOPCs were USD$3766.1 (0y), USD$3795.2 (1-2 ys), USD$4657.7 (3-4 ys), USD$5979.9 (5-8 ys), and USD$5588.7 (9 ys and older) for PKU patients of different age groups. The median economic burden of classical PKU was 75.0 % of total annual family income (range 1.0-779.1 %), and 94.4 % of the families exceeding the threshold considered as catastrophic expenditure. There was a negative correlation between the financial burden and the proportion of time when Phe concentrations were in the desired target range (120-250 μmol/L) in 0-4-ys group (r = -0.474, p = 0.026). The management of PKU is associated with a severe financial burden on patients' families, which may lead to insufficient treatment or variation of blood Phe concentration. The current reimbursement policies are as yet inadequate. A national reimbursement system targeting treatment practices for PKU patients and other rare diseases across China is imperative.

  8. Large Neutral Amino Acid Supplementation Exerts Its Effect through Three Synergistic Mechanisms: Proof of Principle in Phenylketonuria Mice

    PubMed Central

    van Vliet, Danique; Bruinenberg, Vibeke M.; Mazzola, Priscila N.; van Faassen, Martijn H. J. R.; de Blaauw, Pim; Kema, Ido P.; Heiner-Fokkema, M. Rebecca; van Anholt, Rogier D.; van der Zee, Eddy A.; van Spronsen, Francjan J.

    2015-01-01

    Background Phenylketonuria (PKU) was the first disorder in which severe neurocognitive dysfunction could be prevented by dietary treatment. However, despite this effect, neuropsychological outcome in PKU still remains suboptimal and the phenylalanine-restricted diet is very demanding. To improve neuropsychological outcome and relieve the dietary restrictions for PKU patients, supplementation of large neutral amino acids (LNAA) is suggested as alternative treatment strategy that might correct all brain biochemical disturbances caused by high blood phenylalanine, and thereby improve neurocognitive functioning. Objective As a proof-of-principle, this study aimed to investigate all hypothesized biochemical treatment objectives of LNAA supplementation (normalizing brain phenylalanine, non-phenylalanine LNAA, and monoaminergic neurotransmitter concentrations) in PKU mice. Methods C57Bl/6 Pah-enu2 (PKU) mice and wild-type mice received a LNAA supplemented diet, an isonitrogenic/isocaloric high-protein control diet, or normal chow. After six weeks of dietary treatment, blood and brain amino acid and monoaminergic neurotransmitter concentrations were assessed. Results In PKU mice, the investigated LNAA supplementation regimen significantly reduced blood and brain phenylalanine concentrations by 33% and 26%, respectively, compared to normal chow (p<0.01), while alleviating brain deficiencies of some but not all supplemented LNAA. Moreover, LNAA supplementation in PKU mice significantly increased brain serotonin and norepinephrine concentrations from 35% to 71% and from 57% to 86% of wild-type concentrations (p<0.01), respectively, but not brain dopamine concentrations (p = 0.307). Conclusions This study shows that LNAA supplementation without dietary phenylalanine restriction in PKU mice improves brain biochemistry through all three hypothesized biochemical mechanisms. Thereby, these data provide proof-of-concept for LNAA supplementation as a valuable alternative dietary

  9. Sapropterin dihydrochloride for phenylketonuria.

    PubMed

    Somaraju, Usha Rani; Merrin, Marcus

    2010-06-16

    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. To assess the safety and efficacy of sapropterin dihydrochloride in lowering blood phenylalanine concentration in people with phenylketonuria. We identified relevant trials from the Group's Inborn Errors of Metabolism Trials Register. Last search:07 May 2010.We also searched ClinicalTrials.gov and Current controlled trials. Last search: 01 September 2009.We contacted the manufacturers of the drug (BioMarin Pharmaceutical Inc.) for information regarding any unpublished trials. Randomized controlled trials comparing sapropterin with no supplementation or placebo in people with phenylketonuria due to phenylalanine hydroxylase deficiency. Two authors independently assessed trials and extracted outcome data. 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

  10. A comparison of phenylketonuria with attention deficit hyperactivity disorder: do markedly different aetiologies deliver common phenotypes?

    PubMed

    Stevenson, M; McNaughton, N

    2013-10-01

    Phenylketonuria (PKU) is a well-defined metabolic disorder arising from a mutation that disrupts phenylalanine metabolism and so produces a variety of neural changes indirectly. Severe cognitive impairment can be prevented by dietary treatment; however, residual symptoms may be reported. These residual symptoms appear to overlap a more prevalent childhood disorder: Attention Deficit/Hyperactivity Disorder (ADHD). However, the aetiology of ADHD is a vast contrast to PKU: it seems to arise from a complex combination of genes; and it has a substantial environmental component. We ask whether these two disorders result from two vastly different genotypes that converge on a specific core phenotype that includes similar dysfunctions of Gray's (Gray, 1982) Behavioural Inhibition System (BIS), coupled with other disorder-specific dysfunctions. If so, we believe comparison of the commonalities will allow greater understanding of the neuropsychology of both disorders. We review in detail the aetiology, treatment, neural pathology, cognitive deficits and electrophysiological abnormalities of PKU; and compare this with selected directly matching aspects of ADHD. The biochemical and neural pathologies of PKU and ADHD are quite distinct in their causes and detail; but they result in the disorder in the brain of large amino acid levels, dopamine and white matter that are very similar and could explain the overlap of symptoms within and between the PKU and ADHD spectra. The common deficits affect visual function, motor function, attention, working memory, planning, and inhibition. For each of PKU and ADHD separately, a subset of deficits has been attributed to a primary dysfunction of behavioural inhibition. In the case of ADHD (excluding the inattentive subtype) this has been proposed to involve a specific failure of the BIS; and we suggest that this is also true of PKU. This accounts for a substantial proportion of the parallels in the superficial symptoms of both disorders and

  11. Growth and body composition in children with classical phenylketonuria: results in 34 patients and review of the literature.

    PubMed

    Huemer, M; Huemer, C; Möslinger, D; Huter, D; Stöckler-Ipsiroglu, S

    2007-10-01

    Treatment of phenylketonuria (PKU, OMIM 261600) means a diet restricted in natural protein and supplemented with phenylalanine (Phe)-free L-amino acid mixtures. Growth impairment has been described even in patients with a total protein intake at or above the recommended dietary allowance (RDA). In the present study, growth and body composition (fat-free mass (FFM) and fat) were recorded over 12 months in 34 treated PKU patients (mean age 8.7 years at baseline). Measurements were compared with those of healthy peers and with general population standard (Z-) scores calculated using the LMS method. In 28 PKU patients, data on birth weight and birth length were available and related to measurements at baseline of the study. Mean total protein intake in PKU patients was 124% (range 77-193%) of the RDA (DACH 2000). No significant differences in growth and body composition were present between PKU patients and healthy populations either at birth or during the study period. The significant correlation of FFM (representing muscle mass) with intake of natural protein--rather than total protein--indicates that the enhancement of tolerance to natural protein may be of value in PKU patients.

  12. Fish-Free Diet in Patients with Phenylketonuria Is Not Associated with Early Atherosclerotic Changes and Enhanced Platelet Activation.

    PubMed

    Htun, Patrik; Nee, Jens; Ploeckinger, Ursula; Eder, Klaus; Geisler, Tobias; Gawaz, Meinrad; Bocksch, Wolfgang; Fateh-Moghadam, Suzanne

    2015-01-01

    Since patients with phenylketonuria (PKU) have to follow a lifelong restriction of natural protein to lower phenylalanine-intake, they never eat fish. This diet may lead to a chronic deficit of omega-3 and omega-6 fatty acids with the risk of early atherosclerotic changes. The aim of the study was to analyse the fatty acid profile of PKU patients and to correlate the results with surrogate markers of early atherosclerotic changes [enhanced carotid intima media thickness (CIMT) and ß-stiffness index] and platelet activation. In 43 PKU patients and in 58 healthy controls we prospectively examined the fatty acid profile, CIMT, ß-stiffness index and platelet activation (flow cytometric determination of markers of platelet activation). CIMT was measured bilaterally by ultrasound. CIMTmean was defined as the mean value of the sum of CIMTleft and CIMTright. Despite of lower HDL-cholesterol and higher triglyceride concentrations in the PKU group, there was no significant difference in the omega-6 or omega-3 fatty acid profile, CIMT, ß-stiffness index between both groups. Platelet activation was not enhanced in the PKU group. Fish-free diet does not induce early atherosclerotic changes or enhanced platelet activation in PKU patients.

  13. Splice, insertion-deletion and nonsense mutations that perturb the phenylalanine hydroxylase transcript cause phenylketonuria in India.

    PubMed

    Bashyam, Murali D; Chaudhary, Ajay K; Kiran, Manjari; Nagarajaram, Hampapathalu A; Devi, Radha Rama; Ranganath, Prajnya; Dalal, Ashwin; Bashyam, Leena; Gupta, Neerja; Kabra, Madhulika; Muranjan, Mamta; Puri, Ratna D; Verma, Ishwar C; Nampoothiri, Sheela; Kadandale, Jayarama S

    2014-03-01

    Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by mutational inactivation of the phenylalanine hydroxylase (PAH) gene. Missense mutations are the most common PAH mutation type detected in PKU patients worldwide. We performed PAH mutation analysis in 27 suspected Indian PKU families (including 7 from our previous study) followed by structure and function analysis of specific missense and splice/insertion-deletion/nonsense mutations, respectively. Of the 27 families, disease-causing mutations were detected in 25. A total of 20 different mutations were identified of which 7 "unique" mutations accounted for 13 of 25 mutation positive families. The unique mutations detected exclusively in Indian PKU patients included three recurrent mutations detected in three families each. The 20 mutations included only 5 missense mutations in addition to 5 splice, 4 each nonsense and insertion-deletion mutations, a silent variant in coding region and a 3'UTR mutation. One deletion and two nonsense mutations were characterized to confirm significant reduction in mutant transcript levels possibly through activation of nonsense mediated decay. All missense mutations affected conserved amino acid residues and sequence and structure analysis suggested significant perturbations in the enzyme activity of respective mutant proteins. This is probably the first report of identification of a significantly low proportion of missense PAH mutations from PKU families and together with the presence of a high proportion of splice, insertion-deletion, and nonsense mutations, points to a unique PAH mutation profile in Indian PKU patients. © 2013 Wiley Periodicals, Inc.

  14. The discovery of phenylketonuria: the story of a young couple, two retarded children, and a scientist.

    PubMed

    Centerwall, S A; Centerwall, W R

    2000-01-01

    In the 1920s, a little girl 3 years of age was brought from China to the United States by her American mother. Although the child was beautiful, her mind was not developing. The grief-stricken mother had consulted doctors in China, but they could neither diagnose the problem nor provide treatment. Morning and night the same questions occupied her mind: "What is the matter with my little girl? What is causing it? Is there any doctor, anywhere, who can cure her?" In the United States, she also went from doctors to psychologists to clinics looking for someone who could help. Finally, she went to the Mayo Clinic in Rochester, Minnesota. When she had answered all of the doctor's questions, and all the tests were finished, they still could not tell her what was wrong. There was nothing they could do. The disease from which the little girl suffered was unknown at that time. The mother was Pearl Buck. In her book, The Child Who Never Grew,(1) she described her first infant: "I remember when she was only 3 months old she lay in her basket on the sun deck of a ship. I had taken her there for the morning air. The people who promenaded on deck often stopped to look at her, and my pride grew as they spoke of her unusual beauty and of the intelligent look of her deep, blue eyes. I do not know at what moment the growth of her intelligence stopped, nor to this day why it did." This is a classical description of the disease, phenylketonuria (PKU). A perfect infant seems to develop normally for several months, then the development slows and at some point seems to stop. "Look at Mommy-look at Daddy!" the parents say as they try to coax the treasured smiles. Instead, the child drifts into a dream world and into irreversible mental retardation. All Pearl Buck's devotion and determination was of no avail in finding the cause of her child's retardation. It was to be another mother with the same commitment to her beautiful but retarded children, who approximately 10 years later followed

  15. Tyrosine supplementation for phenylketonuria.

    PubMed

    Webster, Diana; Wildgoose, Joanne

    2010-08-04

    Phenylketonuria is an inherited disease for which the main treatment is the dietary restriction of the amino acid phenylalanine. The diet has to be initiated in the neonatal period to prevent or reduce mental handicap. However, the diet is very restrictive and unpalatable and can be difficult to follow. A deficiency of the amino acid tyrosine has been suggested as a cause of some of the neuropsychological problems exhibited in phenylketonuria. Therefore, this review aims to assess the efficacy of tyrosine supplementation for phenylketonuria. To assess the effects of tyrosine supplementation alongside or instead of a phenylalanine-restricted diet for people with phenylketonuria, who commenced on diet at diagnosis and either continued on the diet or relaxed the diet later in life. To assess the evidence that tyrosine supplementation alongside, or instead of a phenylalanine-restricted diet improves intelligence, neuropsychological performance, growth and nutritional status, mortality rate and quality of life. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register which is comprised of references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Additional studies were identified from handsearches of the Journal of Inherited Metabolic Disease (from inception in 1978 to 1998). The manufacturers of prescribable dietary products used in the treatment of phenylketonuria were also contacted for further references.Date of the most recent search of the Group's Inborn Errors of Metabolism Trials Register: 09 June 2010. All randomised or quasi-randomised trials investigating the use of tyrosine supplementation versus placebo in people with phenylketonuria in addition to, or instead of, a phenylalanine-restricted diet. People treated for maternal phenylketonuria were excluded. Two authors independently assessed the trial eligibility, methodological quality

  16. Tyrosine supplementation for phenylketonuria.

    PubMed

    Webster, Diana; Wildgoose, Joanne

    2013-06-05

    Phenylketonuria is an inherited disease for which the main treatment is the dietary restriction of the amino acid phenylalanine. The diet has to be initiated in the neonatal period to prevent or reduce mental handicap. However, the diet is very restrictive and unpalatable and can be difficult to follow. A deficiency of the amino acid tyrosine has been suggested as a cause of some of the neuropsychological problems exhibited in phenylketonuria. Therefore, this review aims to assess the efficacy of tyrosine supplementation for phenylketonuria. To assess the effects of tyrosine supplementation alongside or instead of a phenylalanine-restricted diet for people with phenylketonuria, who commenced on diet at diagnosis and either continued on the diet or relaxed the diet later in life. To assess the evidence that tyrosine supplementation alongside, or instead of a phenylalanine-restricted diet improves intelligence, neuropsychological performance, growth and nutritional status, mortality rate and quality of life. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register which is comprised of references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Additional studies were identified from handsearches of the Journal of Inherited Metabolic Disease (from inception in 1978 to 1998). The manufacturers of prescribable dietary products used in the treatment of phenylketonuria were also contacted for further references.Date of the most recent search of the Group's Inborn Errors of Metabolism Trials Register: 28 June 2012. All randomised or quasi-randomised trials investigating the use of tyrosine supplementation versus placebo in people with phenylketonuria in addition to, or instead of, a phenylalanine-restricted diet. People treated for maternal phenylketonuria were excluded. Two authors independently assessed the trial eligibility, methodological quality

  17. Lower n-3 long-chain polyunsaturated fatty acid values in patients with phenylketonuria: a systematic review and meta-analysis.

    PubMed

    Lohner, Szimonetta; Fekete, Katalin; Decsi, Tamás

    2013-07-01

    The mainstream of phenylketonuria (PKU) management is lifelong restriction of protein intake; however, this dietary restriction may be accompanied by insufficient dietary intake of long-chain polyunsaturated fatty acids (LCPUFA). The objective of this review was to assess whether significant depletion of LCPUFA can be detected in PKU patients on low-protein diet and whether LCPUFA supplementation is an effective way to increase the availability of LCPUFA in PKU patients. The method included structured search strategy on Ovid MEDLINE, Scopus, LILACS, and the Cochrane Library CENTRAL databases, with formal inclusion/exclusion criteria, data extraction procedure, and meta-analysis. We evaluated 9 case-control studies and 6 randomized controlled trials, dated from the inception of the databases to 2012. The meta-analysis of the case-control studies showed significantly lower values of both eicosapentaenoic acid and docosahexaenoic acid (DHA) in all biomarkers investigated and that of arachidonic acid in total plasma lipids in PKU patients as compared with healthy controls. There were sufficient data to demonstrate that dietary DHA supplementation of patients with PKU significantly increases the contribution of DHA to total plasma lipids. In summary, suboptimal LCPUFA status, especially that of n-3 LCPUFA, can be detected in PKU patients. Supplementing DHA to the diet of PKU patients may improve their LCPUFA status; however, further research is needed to determine the optimal supplementation dosage and to establish beneficial functional outcomes. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Behaviour and school achievement in patients with early and continuously treated phenylketonuria.

    PubMed

    Stemerdink, B A; Kalverboer, A F; van der Meere, J J; van der Molen, M W; Huisman, J; de Jong, L W; Slijper, F M; Verkerk, P H; van Spronsen, F J

    2000-09-01

    Thirty patients with early and continuously treated phenylketonuria (PKU) between 8 and 20 years of age were compared with 30 controls, matched individually for age, sex, and educational level of both parents, on behaviour rating scales for parents and teachers as well as a school achievement scale. PKU patients, as a group, demonstrated more problems in task-oriented behaviour and average academic performance than did matched controls. Interestingly, whereas male PKU patients were rated significantly lower on introversion by their teachers, female patients were rated significantly higher on introversion and lower on extraversion than matched controls. This sex difference was also reflected in the relationship between measures of dietary control and the behaviour clusters, suggesting that male and female patients respond differently to elevated Phe levels or the stress associated with PKU. The teacher rating on average academic performance of the PKU patients was associated with recent level of dietary control, which suggests that it might be improved by more strict adherence to the diet. In addition, academic performance correlated negatively with the behaviour cluster negative task orientation. Further studies are recommended to obtain a more complete evaluation of this relationship and to replicate the current findings on larger samples. Over the years a number of studies have examined behaviour and school achievement in patients with early treated phenylketonuria (PKU; McKusick 261600). In general, these studies have found that despite early treatment with a phenylalanine (Phe)-restricted diet, PKU patients demonstrate more behavioural and school problems than do healthy controls. The behaviour problems include both internalizing symptoms (e.g. solitary, unresponsive, anxious, depressed mood: Pietz et al 1997; Smith et al 1988; Weglage et al 1992) and externalizing symptoms (e.g. hyperactive, talkative, impulsive, restless: Hendrikx et al 1994; Kalverboer et al

  19. Sapropterin dihydrochloride for phenylketonuria.

    PubMed

    Somaraju, Usha Rani; Merrin, Marcus

    2015-03-27

    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.  To assess the safety and efficacy of sapropterin dihydrochloride in lowering blood phenylalanine concentration in people with phenylketonuria. 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. Randomized controlled trials comparing sapropterin with no supplementation or placebo in people with phenylketonuria due to phenylalanine hydroxylase deficiency. Two authors independently assessed trials and extracted outcome data. 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

  20. Sapropterin dihydrochloride for phenylketonuria.

    PubMed

    Somaraju, Usha Rani; Merrin, Marcus

    2012-12-12

    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.   To assess the safety and efficacy of sapropterin dihydrochloride in lowering blood phenylalanine concentration in people with phenylketonuria. We identified relevant trials from the Group's Inborn Errors of Metabolism Trials Register. Date of last search: 29 June 2012.We also searched ClinicalTrials.gov and Current controlled trials. Last search: 23 July 2012.We contacted the manufacturers of the drug (BioMarin Pharmaceutical Inc.) for information regarding any unpublished trials. Randomized controlled trials comparing sapropterin with no supplementation or placebo in people with phenylketonuria due to phenylalanine hydroxylase deficiency. Two authors independently assessed trials and extracted outcome data. 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

  1. Parental problem-solving skills, stress, and dietary compliance in phenylketonuria.

    PubMed

    Fehrenbach, A M; Peterson, L

    1989-04-01

    Parents of 30 children with phenylketonuria (PKU) who were classified as being in good dietary control (compliant, measured as within the medically acceptable range of blood phenylalanine levels of 2-10 mg) or poor dietary control (noncompliant, measured as either below or above medically acceptable 2-10 mg blood phenylalanine levels) engaged in verbal and written problem-solving situations under conditions of both high and low time-pressure induced stress. Overall, compliant parents gave higher quality verbal and written problem-solving solutions than noncompliant parents. Stress reduced the quality of problem solving in both compliant and noncompliant parents, but even under high stress, compliant parents demonstrated better problem-solving abilities than noncompliant parents. The potential importance of these findings for preventive intervention in PKU families is discussed.

  2. Phenylketonuria patients' and their parents' knowledge and attitudes to the daily diet - multi-centre study.

    PubMed

    Witalis, Ewa; Mikoluc, Bozena; Motkowski, Radoslaw; Sawicka-Powierza, Jolanta; Chrobot, Agnieszka; Didycz, Bozena; Lange, Agata; Mozrzymas, Renata; Milanowski, Andrzej; Nowacka, Maria; Piotrowska-Depta, Mariola; Romanowska, Hanna; Starostecka, Ewa; Wierzba, Jolanta; Skorniewska, Magdalena; Wojcicka-Bartlomiejczyk, Barbara Iwona; Gizewska, Maria; Car, Halina

    2017-01-01

    The aim of the study was to assess both patients' and their parents' knowledge of phenylketonuria (PKU) treatment and compliance with PKU diet. The study included 173 PKU patients aged 10-19 and 110 parents of PKU children who were enrolled in the study on the basis of questionnaire data. The study also included 45 patients aged ≥20. Our study demonstrated that only 45% (n = 74) of PKU patients knew daily Phe intake recommendations, 27% of patients (n = 41) knew the Phe content in a minimum of three out of four researched food products. Patients' knowledge concerning Phe intake (p = 0.0181) and the knowledge of selected food products (p = 0.041819) improved with age. We did not establish such a correlation in the group of PKU children's parents. Approximately 31% of patients and 22% of parents reported helplessness, which increased with the child's age, associated with the necessity to adhere to the diet; 30% of patients reported feeling ashamed of the fact that they could not eat all food products. Regardless of age, children were more likely than parents to report helplessness (p = 0.032005). Among patients, 41.40% declared that they would wish to select products unassisted but their parents did not permit them to do so. The question of whether parents teach children self-reliance in meal preparation was answered affirmatively by 98% of parents and only 81% of children (p = 0.0001). Our data demonstrated that parents' and children's knowledge concerning treatment recommendations and food products does not have a direct impact on attitude to the PKU diet. Limiting children's independence in meal selection, growing helplessness in the face of dietary adherence and shame resulting from the necessity to follow a different diet observed in PKU families are responsible for shaping and perpetuating a consistently negative attitude to the diet. The care of PKU paediatric patients requires consistent, long-term family and individual therapy which may

  3. The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background

    PubMed Central

    Bruinenberg, Vibeke M.; van der Goot, Els; van Vliet, Danique; de Groot, Martijn J.; Mazzola, Priscila N.; Heiner-Fokkema, M. Rebecca; van Faassen, Martijn; van Spronsen, Francjan J.; van der Zee, Eddy A.

    2016-01-01

    To unravel the role of gene mutations in the healthy and the diseased state, countless studies have tried to link genotype with phenotype. However, over the years, it became clear that the strain of mice can influence these results. Nevertheless, identical gene mutations in different strains are often still considered equals. An example of this, is the research done in phenylketonuria (PKU), an inheritable metabolic disorder. In this field, a PKU mouse model (either on a BTBR or C57Bl/6 background) is often used to examine underlying mechanisms of the disease and/or new treatment strategies. Both strains have a point mutation in the gene coding for the enzyme phenylalanine hydroxylase which causes toxic concentrations of the amino acid phenylalanine in blood and brain, as found in PKU patients. Although the mutation is identical and therefore assumed to equally affect physiology and behavior in both strains, no studies directly compared the two genetic backgrounds to test this assumption. Therefore, this study compared the BTBR and C57Bl/6 wild-type and PKU mice on PKU-relevant amino acid- and neurotransmitter-levels and at a behavioral level. The behavioral paradigms were selected from previous literature on the PKU mouse model and address four domains, namely (1) activity levels, (2) motor performance, (3) anxiety and/or depression-like behavior, and (4) learning and memory. The results of this study showed comparable biochemical changes in phenylalanine and neurotransmitter concentrations. In contrast, clear differences in behavioral outcome between the strains in all four above-mentioned domains were found, most notably in the learning and memory domain. The outcome in this domain seem to be primarily due to factors inherent to the genetic background of the mouse and much less by differences in PKU-specific biochemical parameters in blood and brain. The difference in behavioral outcome between PKU of both strains emphasizes that the consequence of the PAH

  4. The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background.

    PubMed

    Bruinenberg, Vibeke M; van der Goot, Els; van Vliet, Danique; de Groot, Martijn J; Mazzola, Priscila N; Heiner-Fokkema, M Rebecca; van Faassen, Martijn; van Spronsen, Francjan J; van der Zee, Eddy A

    2016-01-01

    To unravel the role of gene mutations in the healthy and the diseased state, countless studies have tried to link genotype with phenotype. However, over the years, it became clear that the strain of mice can influence these results. Nevertheless, identical gene mutations in different strains are often still considered equals. An example of this, is the research done in phenylketonuria (PKU), an inheritable metabolic disorder. In this field, a PKU mouse model (either on a BTBR or C57Bl/6 background) is often used to examine underlying mechanisms of the disease and/or new treatment strategies. Both strains have a point mutation in the gene coding for the enzyme phenylalanine hydroxylase which causes toxic concentrations of the amino acid phenylalanine in blood and brain, as found in PKU patients. Although the mutation is identical and therefore assumed to equally affect physiology and behavior in both strains, no studies directly compared the two genetic backgrounds to test this assumption. Therefore, this study compared the BTBR and C57Bl/6 wild-type and PKU mice on PKU-relevant amino acid- and neurotransmitter-levels and at a behavioral level. The behavioral paradigms were selected from previous literature on the PKU mouse model and address four domains, namely (1) activity levels, (2) motor performance, (3) anxiety and/or depression-like behavior, and (4) learning and memory. The results of this study showed comparable biochemical changes in phenylalanine and neurotransmitter concentrations. In contrast, clear differences in behavioral outcome between the strains in all four above-mentioned domains were found, most notably in the learning and memory domain. The outcome in this domain seem to be primarily due to factors inherent to the genetic background of the mouse and much less by differences in PKU-specific biochemical parameters in blood and brain. The difference in behavioral outcome between PKU of both strains emphasizes that the consequence of the PAH

  5. Founder effect of a prevalent phenylketonuria mutation in the Oriental population

    SciTech Connect

    Wang, Tao Chinese Academy of Medical Sciences, Beijing ); Okano, Yoshiyuki; Eisensmith, R.C.; Harvey, M.L.; Woo, S.L.C. ); Lo, W.H.Y.; Yuan, Lifang ); Huang, Shuzhen; Zeng, Yitao ); Furuyama, Junichi ); Oura, Toshiaki ); Sommer, S.S. )

    1991-03-15

    A missense mutation has been identified in the human phenylalanine hydroxylase Chinese patient with classic phenylketonuria (PKU). A G-to-C transition at the second base of codon 413 in exon 12 of the gene results in the substitution of Pro{sup 413} for Arg{sup 413} in the mutant protein. This mutation (R413P) results in negligible enzymatic activity when expressed in heterologous mammalian cells and is compatible with a classic PKU phenotype in the patient. Population genetic studies reveal that this mutation is tightly linked to restriction fragment length polymorphism haplotype 4, which is the predominant haplotype of the PAH locus in the Oriental population. It accounts for 13.8% of northern Chinese and 27% of Japanese PKU alleles, but it is rare in southern Chinese (2.2%) and is absent in the Caucasian population. The data demonstrate unambiguously that the mutation occurred after racial divergence of Orientals and Caucasians and suggest that the allele has spread throughout the Orient by a founder effect. Previous protein polymorphism studies in eastern Asia have led to the hypothesis that northern Mongoloids represented a founding population in Asia. The results are compatible with this hypothesis in that the PKU mutation might have occurred in northern Mongoloids and subsequently spread to the Chinese and Japanese populations.

  6. Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria

    PubMed Central

    Pey, Angel L.; Ying, Ming; Cremades, Nunilo; Velazquez-Campoy, Adrian; Scherer, Tanja; Thöny, Beat; Sancho, Javier; Martinez, Aurora

    2008-01-01

    Phenylketonuria (PKU) is an inborn error of metabolism caused by mutations in phenylalanine hydroxylase (PAH). Over 500 disease-causing mutations have been identified in humans, most of which result in PAH protein misfolding and increased turnover in vivo. The use of pharmacological chaperones to stabilize or promote correct folding of mutant proteins represents a promising new direction in the treatment of misfolding diseases. We performed a high-throughput ligand screen of over 1,000 pharmacological agents and identified 4 compounds (I–IV) that enhanced the thermal stability of PAH and did not show substantial inhibition of PAH activity. In further studies, compounds III (3-amino-2-benzyl-7-nitro-4-(2-quinolyl)-1,2-dihydroisoquinolin-1-one) and IV (5,6-dimethyl-3-(4-methyl-2-pyridinyl)-2-thioxo-2,3-dihydrothieno[2,3- d]pyrimidin-4(1H)-one) stabilized the functional tetrameric conformation of recombinant WT-PAH and PKU mutants. These compounds also significantly increased activity and steady-state PAH protein levels in cells transiently transfected with either WT-PAH or PKU mutants. Furthermore, PAH activity in mouse liver increased after a 12-day oral administration of low doses of compounds III and IV. Thus, we have identified 2 small molecules that may represent promising alternatives in the treatment of PKU. PMID:18596920

  7. Predictive equations underestimate resting energy expenditure in female adolescents with phenylketonuria

    PubMed Central

    Quirk, Meghan E.; Schmotzer, Brian J.; Schmotzer, Brian J.; Singh, Rani H.

    2010-01-01

    Resting energy expenditure (REE) is often used to estimate total energy needs. The Schofield equation based on weight and height has been reported to underestimate REE in female children with phenylketonuria (PKU). The objective of this observational, cross-sectional study was to evaluate the agreement of measured REE with predicted REE for female adolescents with PKU. A total of 36 females (aged 11.5-18.7 years) with PKU attending Emory University’s Metabolic Camp (June 2002 – June 2008) underwent indirect calorimetry. Measured REE was compared to six predictive equations using paired Student’s t-tests, regression-based analysis, and assessment of clinical accuracy. The differences between measured and predicted REE were modeled against clinical parameters to determine to if a relationship existed. All six selected equations significantly under predicted measured REE (P< 0.005). The Schofield equation based on weight had the greatest level of agreement, with the lowest mean prediction bias (144 kcal) and highest concordance correlation coefficient (0.626). However, the Schofield equation based on weight lacked clinical accuracy, predicting measured REE within ±10% in only 14 of 36 participants. Clinical parameters were not associated with bias for any of the equations. Predictive equations underestimated measured REE in this group of female adolescents with PKU. Currently, there is no accurate and precise alternative for indirect calorimetry in this population. PMID:20497783

  8. Molecular characterisation of phenylketonuria in a Chinese mainland population using next-generation sequencing

    PubMed Central

    Li, Nana; Jia, Haitao; Liu, Zhen; Tao, Jing; Chen, Song; Li, Xiaohong; Deng, Ying; Jin, Xi; Song, Jiaping; Zhang, Liangtao; Liang, Yu; Wang, Wei; Zhu, Jun

    2015-01-01

    Phenylketonuria (PKU) is an inherited autosomal recessive disorder of phenylalanine metabolism, mainly caused by a deficiency of phenylalanine hydroxylase (PAH). The incidence of various PAH mutations differs among race and ethnicity. Here we report a spectrum of PAH mutations complied from 796 PKU patients from mainland China. The all 13 exons and adjacent intronic regions of the PAH gene were determined by next-generation sequencing. We identified 194 different mutations, of which 41 are not reported before. Several mutations reoccurred with high frequency including p.R243Q, p.EX6-96A > G, p.V399V, p.R241C, p.R111*, p.Y356*, p.R413P, and IVS4-1G > A. 76.33% of mutations were localized in exons 3, 6, 7, 11, 12. We further compared the frequency of each mutation between populations in northern and southern China, and found significant differences in 19 mutations. Furthermore, we identified 101 mutations that are not reported before in Chinese population, our study thus broadens the mutational spectrum of Chinese PKU patients. Additionally, 41 novel mutations will expand and improve PAH mutation database. Finally, our study offers proof that NGS is effective, reduces screening times and costs, and facilitates the provision of appropriate genetic counseling for PKU patients. PMID:26503515

  9. Epilepsy and phenylketonuria: a case description and EEG-fMRI findings

    PubMed Central

    Guida, Melania; Pesaresi, Ilaria; Fabbri, Serena; Sartucci, Ferdinando; Cosottini, Mirco; Giorgi, Filippo Sean

    2014-01-01

    Summary Phenylketonuria (PKU) is characterized by phenylalanine accumulation due to phenylalanine hydroxylase deficiency. Up to 50% of PKU patients experience seizures. We evaluated an adult PKU patient who suffered from absences and primarily generalized tonic-clonic seizures, associated with generalized spike-and-wave discharges (GSWs) on EEG. An analysis of blood oxygenation level-dependent (BOLD) signal changes during interictal epileptiform discharges showed early activation of the left perirolandic cortex followed by a BOLD signal decrease within cortical regions belonging to the default mode network and left frontoparietal cortex. Moreover, deactivation of the head of the right caudate nucleus and the left thalamus was observed. The fMRI pattern observed in our patient during GSWs is similar but not identical to that observed in idiopathic generalized epilepsy, suggesting different neurophysiological mechanisms. This is the first description of BOLD-fMRI patterns in a PKU patient with epilepsy. Similar studies in more patients might help to uncover the pathophysiology of seizures in this disease. PMID:25014052

  10. Mutation spectrum of phenylketonuria in Syrian population: genotype-phenotype correlation.

    PubMed

    Murad, Hossam; Dabboul, Amir; Moassas, Faten; Alasmar, Diana; Al-Achkar, Walid

    2013-10-10

    Characterization of the molecular basis of phenylketonuria (PKU) in Syria has been accomplished through the analysis of 78 unrelated chromosomes from 39 Syrian patients with PKU. Phenylalanine hydroxylase (PAH) gene mutations have been analyzed by using molecular detection methods based on the restriction fragment length polymorphism (RFLP), artificial constructed restriction sites (ACRS) PCR and direct DNA sequencing. 56.4% of the patients had cPKU. A mutation detection rate of 79.49% was achieved and sixteen different mutations were found: missense 56.25%, splice site 37.5%, and frameshift 6.25%. The predominant mutation in this population sample was p.R261Q G>A, p.F55>Lfs and p.R243Q G>A. No mutation in six PKU patients was observed. In 57.9% of patient genotypes, the metabolic phenotype could be predicted. The identification of the mutations in the PAH gene and the genotype-phenotype correlation should facilitate the evaluation of metabolic phenotypes, diagnosis, implementation of optimal dietary therapy, and determination of prognosis in the patients and genetic counseling for the patient's relatives.

  11. Molecular characterisation of phenylketonuria in a Chinese mainland population using next-generation sequencing.

    PubMed

    Li, Nana; Jia, Haitao; Liu, Zhen; Tao, Jing; Chen, Song; Li, Xiaohong; Deng, Ying; Jin, Xi; Song, Jiaping; Zhang, Liangtao; Liang, Yu; Wang, Wei; Zhu, Jun

    2015-10-27

    Phenylketonuria (PKU) is an inherited autosomal recessive disorder of phenylalanine metabolism, mainly caused by a deficiency of phenylalanine hydroxylase (PAH). The incidence of various PAH mutations differs among race and ethnicity. Here we report a spectrum of PAH mutations complied from 796 PKU patients from mainland China. The all 13 exons and adjacent intronic regions of the PAH gene were determined by next-generation sequencing. We identified 194 different mutations, of which 41 are not reported before. Several mutations reoccurred with high frequency including p.R243Q, p.EX6-96A > G, p.V399V, p.R241C, p.R111*, p.Y356*, p.R413P, and IVS4-1G > A. 76.33% of mutations were localized in exons 3, 6, 7, 11, 12. We further compared the frequency of each mutation between populations in northern and southern China, and found significant differences in 19 mutations. Furthermore, we identified 101 mutations that are not reported before in Chinese population, our study thus broadens the mutational spectrum of Chinese PKU patients. Additionally, 41 novel mutations will expand and improve PAH mutation database. Finally, our study offers proof that NGS is effective, reduces screening times and costs, and facilitates the provision of appropriate genetic counseling for PKU patients.

  12. Phenylalanine hydroxylase gene mutations in the United States: Report from the maternal PKU collaborative study

    SciTech Connect

    Guldberg, P.; Henriksen, K.F.; Guettler, F.

    1996-07-01

    The major cause of hyperphenylalaninemia is mutations in the gene encoding phenylalanine hydroxylase (PAH). The known mutations have been identified primarily in European patients. The purpose of this study was to determine the spectrum of mutations responsible for PAH deficiency in the United States. One hundred forty-nine patients enrolled in the Maternal PKU Collaborative Study were subjects for clinical and molecular investigations. PAH gene mutations associated with phenylketonuria (PKU) or mild hyperphenylalaninemia (MHP) were identified on 279 of 294 independent mutant chromosomes, a diagnostic efficiency of 95%. The spectrum is composed of 71 different mutations, including 47 missense mutations, 11 splice mutations, 5 nonsense mutations, and 8 microdeletions. Sixteen previously unreported mutations were identified. Among the novel mutations, five were found in patients with MHP, and the remainder were found in patients with PKU. The most common mutations were R408W, IVS12nt1g{r_arrow}a, and Y414C, accounting for 18.7%, 7.8% and 5.4% of the mutant chromosomes, respectively. Thirteen mutations had relative frequencies of 1%-5%, and 55 mutations each had frequencies {le}1%. The mutational spectrum corresponded to that observed for the European ancestry of the U.S. population. To evaluate the extent of allelic variation at the PAH locus within the United States in comparison with other populations, we used allele frequencies to calculate the homozygosity for 11 populations where >90% ascertainment has been obtained. The United States was shown to contain one of the most heterogeneous populations, with homozygosity values similar to Sicily and ethnically mixed sample populations in Europe. The extent of allelic heterogeneity must be a major determining factor in the choice of mutation-detection methodology for molecular diagnosis in PAH deficiency. 47 refs., 1 fig., 5 tabs.

  13. The Impact of Phenylalanine Levels on Cognitive Outcomes in Adults With Phenylketonuria: Effects Across Tasks and Developmental Stages

    PubMed Central

    2017-01-01

    Objective: Phenylketonuria (PKU) is due to an inability to metabolize the amino acid phenylalanine (Phe), leading to its accumulation in the brain. Phe levels can be controlled following a protein-free diet, but cognitive impairments are still present. A number of questions remain to be answered related to which type of metabolic control is important, the age when it is important, the cognitive functions which are most affected and, the best tests to use to monitor cognitive health. Method: We investigated the impact of metabolic control at different ages on cognitive performance in 37 early treated adults with PKU. Results: (a) Phe variation was as associated to performance as average Phe showing that stable dietary control is as important as strict control; (b) For some tasks, current and adult Phe were stronger predictors of performance than childhood or adolescent Phe, showing the importance of a strict diet even in adulthood; and (c) The relationship between performance and Phe levels varied depending on time and cognitive domain. For some functions (sustained attention, visuomotor coordination), Phe at the time of testing was the best predictor. While for other functions (visual attention, executive functions) there was a diminishing or stable relationship across time. Conclusion: Results show the importance of selecting the right tasks to monitor outcomes across ages, but also that the impact of bio-chemical disruptions is different for different functions, at different ages. We show how inherited metabolic diseases offer us a unique vantage point to inform our understanding of brain development and functioning. PMID:28240926

  14. The impact of phenylalanine levels on cognitive outcomes in adults with phenylketonuria: Effects across tasks and developmental stages.

    PubMed

    Romani, Cristina; Palermo, Liana; MacDonald, Anita; Limback, Ellie; Hall, S Kate; Geberhiwot, Tarekegn

    2017-03-01

    Phenylketonuria (PKU) is due to an inability to metabolize the amino acid phenylalanine (Phe), leading to its accumulation in the brain. Phe levels can be controlled following a protein-free diet, but cognitive impairments are still present. A number of questions remain to be answered related to which type of metabolic control is important, the age when it is important, the cognitive functions which are most affected and, the best tests to use to monitor cognitive health. We investigated the impact of metabolic control at different ages on cognitive performance in 37 early treated adults with PKU. (a) Phe variation was as associated to performance as average Phe showing that stable dietary control is as important as strict control; (b) For some tasks, current and adult Phe were stronger predictors of performance than childhood or adolescent Phe, showing the importance of a strict diet even in adulthood; and (c) The relationship between performance and Phe levels varied depending on time and cognitive domain. For some functions (sustained attention, visuomotor coordination), Phe at the time of testing was the best predictor. While for other functions (visual attention, executive functions) there was a diminishing or stable relationship across time. Results show the importance of selecting the right tasks to monitor outcomes across ages, but also that the impact of bio-chemical disruptions is different for different functions, at different ages. We show how inherited metabolic diseases offer us a unique vantage point to inform our understanding of brain development and functioning. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  15. Sapropterin treatment does not enhance the health-related quality of life of patients with phenylketonuria and their parents.

    PubMed

    Feldmann, Reinhold; Wolfgart, Eva; Weglage, Josef; Rutsch, Frank

    2017-06-01

    Sapropterin causes reductions in blood phenylalanine concentrations in sensitive patients with phenylketonuria (PKU). We examined whether the subsequent relaxation of dietary restrictions influenced the quality of life (QoL) of patients and parents. The study cohort comprised 112 patients with PKU followed at the metabolic centre at Münster University Children's Hospital, Germany, from 2012 to 2015. A sapropterin response was defined as a ≥30% reduction in blood phenylalanine levels. The QoL of 38 children and adolescents from the study cohort, with a mean age of 12.4 (range 6.6-18.7) years, was assessed in an outpatient setting and 49 parents of children with PKU also commented on their child's QoL and their own. The participants' QoL was assessed before the start of therapy, and again after six months, using self-report questionnaires. After six months of continuous therapy or diet, QoL was largely unchanged in the patients, according to their self-reports and the parental reports. QoL also remained unchanged in the parents. Sapropterin did not seem to improve QoL in PKU patients and their parents. Patients with PKU had already reached high levels of QoL following classic diets, and these levels were not easily improved by sapropterin. ©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  16. Phenylketonuria mutation analysis in Northern Ireland: A rapid stepwise approach

    SciTech Connect

    Zschocke, J.; Graham, C.A.; Nevin, N.C.

    1995-12-01

    We present a multistep approach for the rapid analysis of phenylketonuria (PKU) mutations. In the first step, three common mutations and a polymorphic short tandem repeat (STR) system are rapidly analyzed with a fluorescent multiplex assay. In the second step, minihaplotypes combining STR and VNTR data are used to determine rare mutations likely to be present in an investigated patient, which are then confirmed by restriction enzyme analysis. The remaining mutations are analyzed with denaturant gradient-gel electrophoresis and sequencing. The first two steps together identify both mutations in 90%-95% of PKU patients, and results can be obtained within 2 d. We have investigated 121 Northern Irish families with hyperphenylalaninemia, including virtually all patients born since 1972, and have found 34 different mutations on 241 of the 242 mutant alleles. Three mutations (R408W, 165T, and F39L) account for 57.5% of mutations, while 14 mutations occur with a frequency of 1%-6%. The present analysis system is efficient and inexpensive and is particularly well suited to routine mutation analysis in a diagnostic setting. 19 refs., 5 tabs.

  17. Depression and anxiety among parents of phenylketonuria children

    PubMed Central

    Gunduz, Mehmet; Arslan, Nur; Unal, Ozlem; Cakar, Sevim; Kuyum, Pınar; Bulbul, Selda F.

    2015-01-01

    Objective: To investigate the existence of depression and/or anxiety with underlying risk factors among parents of children with classical phenylketonuria (PKU). Methods: This cross-sectional study was conducted in the Division of Pediatric Metabolism, Ankara Children’s Hospital, Dokuz Eylul University, Kırıkkale University, and Erzurum Local Research Hospital, Turkey, between January and July 2014. Parents of 61 patients and 36 healthy controls completed the self-report questionnaires. We used Beck Depression Inventory (BDI) to assess the parental depression and State-Trait Anxiety Inventory S-T (STAI S-T) to assess parental anxiety. Results: Depression and anxiety scores were significantly higher in the case group (BDI 12.3±9.1; STAI-S: 38.2±9.6; STAI-T: 43.2±6.9) than controls (BDI: 5.4±4.1 p=0.000; STAI-S: 31.8±7.6 p=0.001; STAI-T: 37.0±7.2 p=0.000). Mothers of the patients had higher scores than the other parental groups (BDI: p=0.000, STAI-S: p=0.001 and STAI-T: p=0.000). Logistic regression analysis showed that low educational level of the parent was the only independent factor for depression (OR 9.96, 95% CI: 1.89-52.35, p=0.007) and state anxiety (OR: 6.99, 95% CI: 1.22-40.48, p=0.030) in the case group. Conclusion: A subset of parents with PKU patients have an anxiety or depressive disorder. Supportive services dealing with the parents of chronically ill children such as PKU are needed in order to reduce the level of anxiety. PMID:26492114

  18. Randomized controlled trial of a protein substitute with prolonged release on the protein status of children with phenylketonuria.

    PubMed

    Giovannini, Marcello; Riva, Enrica; Salvatici, Elisabetta; Cefalo, Graziella; Radaelli, Giovanni

    2014-01-01

    To examine whether a phenylalanine-free protein substitute with prolonged release may be beneficial to the protein status of children with phenylketonuria (PKU) compared to conventional substitutes. Sixty children with PKU, 7 to 16 years of age, were randomly allocated to receive either a prolonged-release (test) or the current conventional protein substitute for 30 days. Subjects were additionally sex and age matched with 60 subjects with mild hyperphenylalaninemia and 60 unaffected subjects. The protein status in children with PKU was assessed by albumin, transthyretin, and retinol-binding protein (RBP), and changes throughout the trial period were the primary outcome measures. Children with PKU did not differ in anthropometry from children with mild hyperphenylalaninemia or unaffected children but they ingested lower amounts of proteins (p < 0.01). No differences occurred throughout the trial between or within children with PKU who received the test or conventional substitute for macronutrient intake. Albumin and RBP concentrations were within the age-specific reference range for all children. The rate of protein insufficiency (transthyretin concentration less than 20 mg/dL) did not differ statistically between children receiving test or conventional substitute (recruitment 51.8% vs 53.6%; end of the trial 44.4% vs 50.0%) but mean transthyretin recovered over 20 mg/dL in children who received the test substitute, increasing from 19.1 to 20.7 mg/dL (mean change, 1.6 mg/dL; 95% confidence interval 0.4 to 2.8 mg/dL). In children receiving conventional substitute mean transthyretin changed from 19.0 to 19.2 mg/dL (0.2; -0.2 to 0.6) mg/dL. Protein substitutes with prolonged release might be beneficial to protein status in children with phenylketonuria.

  19. A Specific Nutrient Combination Attenuates the Reduced Expression of PSD-95 in the Proximal Dendrites of Hippocampal Cell Body Layers in a Mouse Model of Phenylketonuria

    PubMed Central

    Bruinenberg, Vibeke M.; van Vliet, Danique; Attali, Amos; de Wilde, Martijn C.; Kuhn, Mirjam; van Spronsen, Francjan J.; van der Zee, Eddy A.

    2016-01-01

    The inherited metabolic disease phenylketonuria (PKU) is characterized by increased concentrations of phenylalanine in the blood and brain, and as a consequence neurotransmitter metabolism, white matter, and synapse functioning are affected. A specific nutrient combination (SNC) has been shown to improve synapse formation, morphology and function. This could become an interesting new nutritional approach for PKU. To assess whether treatment with SNC can affect synapses, we treated PKU mice with SNC or an isocaloric control diet and wild-type (WT) mice with an isocaloric control for 12 weeks, starting at postnatal day 31. Immunostaining for post-synaptic density protein 95 (PSD-95), a post-synaptic density marker, was carried out in the hippocampus, striatum and prefrontal cortex. Compared to WT mice on normal chow without SNC, PKU mice on the isocaloric control showed a significant reduction in PSD-95 expression in the hippocampus, specifically in the granular cell layer of the dentate gyrus, with a similar trend seen in the cornus ammonis 1 (CA1) and cornus ammonis 3 (CA3) pyramidal cell layer. No differences were found in the striatum or prefrontal cortex. PKU mice on a diet supplemented with SNC showed improved expression of PSD-95 in the hippocampus. This study gives the first indication that SNC supplementation has a positive effect on hippocampal synaptic deficits in PKU mice. PMID:27102170

  20. A randomized, placebo-controlled, double-blind study of sapropterin to treat ADHD symptoms and executive function impairment in children and adults with sapropterin-responsive phenylketonuria.

    PubMed

    Burton, B; Grant, M; Feigenbaum, A; Singh, R; Hendren, R; Siriwardena, K; Phillips, J; Sanchez-Valle, A; Waisbren, S; Gillis, J; Prasad, S; Merilainen, M; Lang, W; Zhang, C; Yu, S; Stahl, S

    2015-03-01

    Symptoms of attention deficit-hyperactivity disorder (ADHD), particularly inattention, and impairments in executive functioning have been reported in early and continuously treated children, adolescents, and adults with phenylketonuria (PKU). In addition, higher blood phenylalanine (Phe) levels have been correlated with the presence of ADHD symptoms and executive functioning impairment. The placebo-controlled PKU ASCEND study evaluated the effects of sapropterin therapy on PKU-associated symptoms of ADHD and executive and global functioning in individuals who had a therapeutic blood Phe response to sapropterin therapy. The presence of ADHD inattentive symptoms and executive functioning deficits was confirmed in this large cohort of 206 children and adults with PKU, of whom 118 responded to sapropterin therapy. In the 38 individuals with sapropterin-responsive PKU and ADHD symptoms at baseline, sapropterin therapy resulted in a significant improvement in ADHD inattentive symptoms in the first 4 weeks of treatment, and improvements were maintained throughout the 26 weeks of treatment. Sapropterin was well-tolerated with a favorable safety profile. The improvements in ADHD inattentive symptoms and aspects of executive functioning in response to sapropterin therapy noted in a large cohort of individuals with PKU indicate that these symptoms are potentially reversible when blood Phe levels are reduced. Copyright © 2014. Published by Elsevier Inc.

  1. A Specific Nutrient Combination Attenuates the Reduced Expression of PSD-95 in the Proximal Dendrites of Hippocampal Cell Body Layers in a Mouse Model of Phenylketonuria.

    PubMed

    Bruinenberg, Vibeke M; van Vliet, Danique; Attali, Amos; de Wilde, Martijn C; Kuhn, Mirjam; van Spronsen, Francjan J; van der Zee, Eddy A

    2016-03-26

    The inherited metabolic disease phenylketonuria (PKU) is characterized by increased concentrations of phenylalanine in the blood and brain, and as a consequence neurotransmitter metabolism, white matter, and synapse functioning are affected. A specific nutrient combination (SNC) has been shown to improve synapse formation, morphology and function. This could become an interesting new nutritional approach for PKU. To assess whether treatment with SNC can affect synapses, we treated PKU mice with SNC or an isocaloric control diet and wild-type (WT) mice with an isocaloric control for 12 weeks, starting at postnatal day 31. Immunostaining for post-synaptic density protein 95 (PSD-95), a post-synaptic density marker, was carried out in the hippocampus, striatum and prefrontal cortex. Compared to WT mice on normal chow without SNC, PKU mice on the isocaloric control showed a significant reduction in PSD-95 expression in the hippocampus, specifically in the granular cell layer of the dentate gyrus, with a similar trend seen in the cornus ammonis 1 (CA1) and cornus ammonis 3 (CA3) pyramidal cell layer. No differences were found in the striatum or prefrontal cortex. PKU mice on a diet supplemented with SNC showed improved expression of PSD-95 in the hippocampus. This study gives the first indication that SNC supplementation has a positive effect on hippocampal synaptic deficits in PKU mice.

  2. Energy recovery transport design for PKU FEL

    SciTech Connect

    Guimei Wang; Yu-Chiu Chao; KUI Zhao; Xiangyang Lu; Jiejia Zhuang; Chuyu Liu; Zhenchao Liu; Jiaer Chen

    2007-06-25

    A free-electron laser based on superconducting linac is under construction in Peking University(PKU). To increase FEL output power, energy recovery is chosen as one of the most potential and popular way. The design of beam transport system for energy recovery is presented, which is suitable for Peking University construction area. Especially, a chicane structure is chosen to change path length at +/-18 degree and R56 in the arc is adjusted for fully bunch compression.

  3. [Diagnostics and treatment of phenylketonuria].

    PubMed

    Bayat, Allan; Møller, Libeth Birk; Lund, Allan Meldgaard

    2015-02-16

    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.

  4. Nutritional status in patients with phenylketonuria using glycomacropeptide as their major protein source.

    PubMed

    Pinto, A; Almeida, M F; Ramos, P C; Rocha, S; Guimas, A; Ribeiro, R; Martins, E; Bandeira, A; MacDonald, A; Rocha, J C

    2017-10-01

    Low phenylalanine (PHE), glycomacropeptide-based protein substitute (GMP) is an alternative to traditional L-amino acid supplements (AA) used in the dietary management of phenylketonuria (PKU). In a retrospective, longitudinal study, we report the nutritional status of PKU patients taking AA and GMP. Eleven PKU patients aged 27±10 years (1 HPA, 4 mild and 6 classical PKU) on dietary treatment were evaluated (anthropometry, body composition, blood pressure measurements, biochemical markers including vitamin, mineral, lipids, carbohydrates and protein status/metabolism, and nutritional intake assessment) at two different annual reviews. The mean time taking AA was 13±5 months and GMP 13±7 months. Blood phenylalanine (PHE) and tyrosine (TYR) were analysed before and after GMP introduction. Both GMP and AA protein substitutes provided similar protein equivalent intake (0.85 vs 0.75 g/kg/day, P=0.182). In the GMP group, it contributed 57% (27-100%) of the protein substitute intake (with AA delivering the rest of protein substitute intake), providing an additional 34±12 mg/day PHE. Nutritional intake, anthropometry and body composition measurements were similar in both the groups. Median blood PHE did not change (P=0.594), although values within target range improved (36 vs 46%), but this was not statistically significant. Mean blood TYR increased (52.0±19.2 vs 63.2±25.6 μmol/l, P=0.033), and all biochemical markers remained stable, except for a lower A1C haemoglobin (P=0.011). Partial GMP contribution to total protein substitute intake did not affect nutritional status in patients with PKU. Blood PHE control was not adversely affected. The increased blood TYR after GMP introduction necessitates further study.

  5. Is BRIEF a useful instrument in day to day care of patients with phenylketonuria?

    PubMed

    Liemburg, Geertje B; Jahja, Rianne; van Spronsen, Francjan J; de Sonneville, Leo M J; van der Meere, Jaap J; Bosch, Annet M; Hollak, Carla E M; Rubio-Gozalbo, M Estela; Brouwers, Martijn C G J; Hofstede, Floris C; de Vries, Maaike C; Janssen, Mirian C H; van der Ploeg, Ans T; Langendonk, Janneke G; Huijbregts, Stephan C J

    2015-03-01

    Despite early and continuous treatment many patients with phenylketonuria (PKU) still experience neurocognitive problems. Most problems have been observed in the domain of executive functioning (EF). For regular monitoring of EF, the use of the Behavior Rating Inventory of Executive Function (BRIEF) has been proposed. The aim of this study was to investigate whether the BRIEF is indeed a useful screening instrument in monitoring of adults with PKU. Adult PKU patients (n = 55; mean age 28.3 ± 6.2 years) filled out the BRIEF-A (higher scores=poorer EF) and performed computerized tasks measuring executive functions (inhibition, cognitive flexibility, and working memory). The outcome of the BRIEF-A questionnaire was compared with the neurocognitive outcome as measured by three tasks from the Amsterdam Neuropsychological Tasks (ANT). Forty-two percent of the PKU patients scored in the borderline/clinical range of the BRIEF-A. Six of the 55 patients (11%) scored >1 SD above the normative mean, mostly on the Metacognition Index. With respect to ANT measurements, patients mainly showed deficits in inhibitory control (34-36%) and cognitive flexibility (31-40%) as compared to the general Dutch population. No significant correlations between the two methods were found, which was confirmed with the Bland-Altman approach where no agreement between the two methods was observed. Only with respect to inhibitory control, patients scored significantly worse on both BRIEF-A and ANT classifications. No other associations between classification according to the BRIEF-A and classifications according to the ANT tasks were found. Patients reporting EF problems in daily life are not necessarily those that present with core EF deficits. The results of this study suggest that regular self-administration of the BRIEF-A is not a sufficient way to monitor EF in adult PKU patients. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Reduced availability of brain amines during critical phases of postnatal development in a genetic mouse model of cognitive delay.

    PubMed

    Pascucci, Tiziana; Andolina, Diego; Ventura, Rossella; Puglisi-Allegra, Stefano; Cabib, Simona

    2008-06-27

    Serotonin (5-HT), dopamine (DA) and noradrenaline (NE) play important roles in brain postnatal maturation. Therefore, deficits in brain availability of biogenic amines during critical developmental phases might underlie neurodevelopmental disturbances associated with cognitive impairment. To test this hypothesis we evaluated brain availability of 5-HT, DA and NE, of their immediate precursors 5-hydroxytryptophan and 3,4-dihydroxy-l-phenylalanine, and of large neutral amino acids phenylalanine, tyrosine and tryptophan, in developing PahEnu2 mice, the genetic model of Phenylketonuria (PKU) a cause of severe cognitive delay. We found deficits of brain amine levels in PKU pups between day 14 and 35 of postnatal life, when pups of the healthy background showed developmental peak increases of amines and precursors. 5-HT deficits were most pronounced, were unrelated with brain availability of the amino acid precursor tryptophan, but overlapped with peak brain phenylalanine concentrations and reduced availability of 5-HT direct precursor 5-hydroxytryptophan. These results identify a critical window of brain amine availability susceptible to disturbances in a genetic mouse model of pathological neurodevelopment and suggest a mechanism of interference with brain aminergic synthesis in PKU and non-PKU hyperphenylalaninemia.

  7. [Early diagnosis of phenylketonuria. Follow up of 2 cases].

    PubMed

    Raimann, E; Cornejo, V; Perales, C G; Barros, T; Moraga, M; Colombo, M

    1992-09-01

    A screening program for the early diagnosis of phenylketonuria was initiated 24 months ago in the Servicio de Salud Metropolitano Central. Since then, 2 cases with phenylketonuria have been early diagnosed. These patients started their nutritional treatment, consisting of a phenylalanine restricted diet at 14 and 17 days of age. The children are submitted to periodic medical, anthropometric, neurologic, biochemical and psychometric analysis. With a strict control they maintain phenylalanine plasma levels between 2 and 6 mg%. Both patients have a normal psychomotor development at 4.5 and 6.5 months of age and an anthropometric development at p50 of NCHS.

  8. Child and Parent Attributions in Chronic Pediatric Conditions: Phenylketonuria (PKU) as an Exemplar

    ERIC Educational Resources Information Center

    Antshel, Kevin M.; Brewster, Scott; Waisbren, Susan E.

    2004-01-01

    Background: Attribution theory, self-regulation, self-handicapping and sick role theories all suggest that children with chronic disease may be held to different standards. This study assesses child and parent attributions in pediatric chronic health conditions and addresses how attributional style may be related to treatment adherence. Methods:…

  9. Child and Parent Attributions in Chronic Pediatric Conditions: Phenylketonuria (PKU) as an Exemplar

    ERIC Educational Resources Information Center

    Antshel, Kevin M.; Brewster, Scott; Waisbren, Susan E.

    2004-01-01

    Background: Attribution theory, self-regulation, self-handicapping and sick role theories all suggest that children with chronic disease may be held to different standards. This study assesses child and parent attributions in pediatric chronic health conditions and addresses how attributional style may be related to treatment adherence. Methods:…

  10. Outcomes of referrals to Child Protective Services for medical neglect in patients with phenylketonuria: Experiences at a single treatment center.

    PubMed

    Bannick, Allison A; Laufman, Jason D; Edwards, Heidi L; Ventimiglia, June; Feldman, Gerald L

    2015-08-01

    Phenylketonuria (PKU) results in an accumulation of phenylalanine (phe) in the blood which can lead to multiple health consequences in affected individuals. Treatment for PKU is available; however adherence to medical management recommendations can be difficult. When recommendations are not followed and the health of a child is at risk, one intervention that may be necessary is a referral for medical neglect to the local child protective services (CPS) agency. This study summarizes the cases that were referred from our metabolic clinic at the Children's Hospital of Michigan to CPS, and the outcomes of that intervention. CPS referrals helped to improve adherence to medical management recommendations in the majority of cases, including a lower blood phe level for the child; however, at times that improvement did not occur until after a second referral and/or the child's temporary removal from the home. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Quality of Life (QoL) assessment in a cohort of patients with phenylketonuria.

    PubMed

    Cazzorla, Chiara; Cegolon, Luca; Burlina, Alessandro P; Celato, Andrea; Massa, Pamela; Giordano, Laura; Polo, Giulia; Daniele, Aurora; Salvatore, Francesco; Burlina, Alberto B

    2014-12-04

    Phenylketonuria (PKU) is a chronic inborn error of amino acid metabolism that requires lifelong follow-up and intervention, which may represent strains on Quality of Life (QoL). This observational study evaluated QoL in a cohort of PKU patients, using updated and detailed instruments. 22 patients with mild PKU respondent to BH4 and 21 patients with classical PKU treated with diet were recruited in this study. Adult patients completed WHOQOL questionnaire-100 (WHOQOL-100) and pediatric patients the Pediatric QoL inventory (PedsQL(TM)). Psychiatric and mood disorders were also evaluated using TAD or BDI and STAI-Y inventories. A multivariable linear regression model was fitted to investigate the predictors of QoL, including age, sex, treatment type, length of current treatment, educational level and employment status (only for adults) as covariates. Results were presented as regression coefficients with 95% confidence interval. Global QoL scores were within normal range both in patients with mild and classical disease but global QoL scores were significantly higher in patients with mild PKU under BH4 treatment as compared to those affected by classical disease who were under diet regimen. Furthermore, QoL significantly increased in long treated PKU patients. Among adult patients, QoL scores were significantly lower in males, in patients with lower education and in those employed or unemployed as compared to students (baseline). Both diet and medical treatment based upon BH4 seem to be associated with higher QoL in the long run. However, patients with mild PKU can rely on BH4 to achieve a higher Phe tolerance and a better compliance to therapy due to diet relaxation/avoidance. Some specific categories of patients with a lower QoL should be investigated more in depth, engaging with those at risk of lower treatment compliance. The questionnaires employed in the present study seemed to be able to effectively detect criticalities in QoL assessment and represent an advance

  12. Ten years of specialized adult care for phenylketonuria - a single-centre experience.

    PubMed

    Mütze, Ulrike; Thiele, Alena Gerlinde; Baerwald, Christoph; Ceglarek, Uta; Kiess, Wieland; Beblo, Skadi

    2016-03-24

    Specialized adult care of phenylketonuria (PKU) patients is of increasing importance. Adult outpatient clinics for inherited errors of metabolism can help to achieve this task, but experience is limited. Ten years after establishment of a coordinated transition process and specialised adult care for inherited metabolic diseases, adult PKU care was evaluated with respect to metabolic control, therapy satisfaction, life satisfaction, sociodemographic data, economical welfare as well as pregnancy outcome. All PKU patients transferred from paediatric to adult care between 2005 and 2015 were identified. A retrospective data analysis and a cross-sectional survey in a sub-cohort of 30 patients including a questionnaire for assessing quality of life (FLZm) were performed as a single-centre investigation at the metabolic department of the University Hospital Leipzig, Germany. For statistical analysis, Mann-Whitney-U-test, t-test for independent samples, ANOVA and chi square test were used as appropriate. 96 PKU patients (56 females/40 males; median age 32 years, range 18-62) were included. In the last 3-year period, 81% of the transferred patients still kept contact to the adult care centre. Metabolic control was stable over the evaluation period and dried blood phenylalanine concentrations mostly remained within the therapeutic range (median 673.0 μmol/l, range 213.0-1381.1). Sociodemographic data, economical welfare and life satisfaction data were comparable to data from the general population. However, differences could be revealed when splitting the cohort according to time of diagnosis and to management during childhood. 83% of the PKU adults were satisfied with the transition process and current adult care. 25 completed pregnancies were supervised; three newborns, born after unplanned pregnancy, showed characteristic symptoms of maternal PKU syndrome. Continuous care for adult PKU patients in a specialized outpatient clinic is successful, leading to good to

  13. Minimally invasive (13)C-breath test to examine phenylalanine metabolism in children with phenylketonuria.

    PubMed

    Turki, Abrar; Murthy, Gayathri; Ueda, Keiko; Cheng, Barbara; Giezen, Alette; Stockler-Ipsiroglu, Sylvia; Elango, Rajavel

    2015-01-01

    Phenylketonuria (PKU) is an autosomal recessive disorder caused by deficiency of hepatic phenylalanine hydroxylase (PAH) leading to increased levels of phenylalanine in the plasma. Phenylalanine levels and phenylalanine hydroxylase (PAH) activity monitoring are currently limited to conventional blood dot testing. 1-(13)C-phenylalanine, a stable isotope can be used to examine phenylalanine metabolism, as the conversion of phenylalanine to tyrosine occurs in vivo via PAH and subsequently releases the carboxyl labeled (13)C as (13)CO2 in breath. Our objective was to examine phenylalanine metabolism in children with PKU using a minimally-invasive 1-(13)C-phenylalanine breath test ((13)C-PBT). Nine children (7 M: 2 F, mean age 12.5 ± 2.87 y) with PKU participated in the study twice: once before and once after sapropterin supplementation. Children were provided 6 mg/kg oral dose of 1-(13)C-phenylalanine and breath samples were collected at 20 min intervals for a period of 2h. Rate of CO2 production was measured at 60 min post-oral dose using indirect calorimetry. The percentage of 1-(13)C-phenylalanine exhaled as (13)CO2 was measured over a 2h period. Prior to studying children with PKU, we tested the study protocol in healthy children (n = 6; 4M: 2F, mean age 10.2 ± 2.48 y) as proof of principle. Production of a peak enrichment (Cmax) of (13)CO2 (% of dose) in all healthy children occurred at 20 min ranging from 17-29% of dose, with a subsequent return to ~5% by the end of 2h. Production of (13)CO2 from 1-(13)C-phenylalanine in all children with PKU prior to sapropterin treatment remained low. Following sapropterin supplementation for a week, production of (13)CO2 significantly increased in five children with a subsequent decline in blood phenylalanine levels, suggesting improved PAH activity. Sapropterin treatment was not effective in three children whose (13)CO2 production remained unchanged, and did not show a reduction in blood phenylalanine levels and improvement

  14. Diagnostic and management practices for phenylketonuria in 19 countries of the South and Eastern European Region: survey results.

    PubMed

    Giżewska, Maria; MacDonald, Anita; Bélanger-Quintana, Amaya; Burlina, Alberto; Cleary, Maureen; Coşkun, Turgay; Feillet, François; Muntau, Ania C; Trefz, Friedrich K; van Spronsen, Francjan J; Blau, Nenad

    2016-02-01

    To avoid potentially severe outcomes, phenylketonuria (PKU) must be detected as soon as possible after birth and managed with life-long treatment. A questionnaire-based survey was performed to document diagnosis and management practices for PKU in a region of Southern and Eastern Europe. Prevalence and management data were obtained from 37/59 (63 %) centres within 19/22 (86%) contacted countries (N = 8600 patients). The main results' analysis was based on completed questionnaires obtained from 31 centres (53%) within 15 countries (68%). A median of 10 % of patients per centre had been diagnosed after the newborn period. Metabolic dieticians and specialised adult PKU clinics were lacking in 36 and 84% of centres, respectively. In 26% of centres, treatment initiation was delayed until >15 days of life. Blood phenylalanine (Phe) thresholds to start treatment and upper Phe targets were inconsistent across centres. Ten percent of centres reported monitoring Phe every 2 weeks for pregnant women with PKU, which is insufficient to minimise risk of neonatal sequalae. Sapropterin dihydrochloride treatment was available in 48% of centres, with 24-h responsiveness tests most common (36%). Only one centre among the five countries lacking newborn screening provided a completed questionnaire. Targeted efforts by health care professionals and governments are needed to optimise diagnostic and management approaches for PKU in Southern and Eastern Europe. PKU must be detected early and optimally managed throughout life to avoid poor outcomes, yet newborn screening is not universal and diagnostic and management practices for PKU are known to vary widely between different centres and countries. Targeted efforts by health care professionals and governments are needed to optimise diagnostic and management approaches. PKU management practices are documented in 19 South and Eastern European countries indicating a heterogeneous situation across the region. Key areas for improvement

  15. Institutionalizing China's Research University through Academic Mobility: The Case of PKU

    ERIC Educational Resources Information Center

    Xiaoguang, Shi

    2015-01-01

    Academic mobility is becoming a tread in academic life and a professional development globally, regionally and nationally. This article makes use of a case university--Peking University (PKU)--as an analytical approach to explore how and why academic mobility can happen in China's research universities. The author first presents an overview of the…

  16. Institutionalizing China's Research University through Academic Mobility: The Case of PKU

    ERIC Educational Resources Information Center

    Xiaoguang, Shi

    2015-01-01

    Academic mobility is becoming a tread in academic life and a professional development globally, regionally and nationally. This article makes use of a case university--Peking University (PKU)--as an analytical approach to explore how and why academic mobility can happen in China's research universities. The author first presents an overview of the…

  17. Pilot study to evaluate the effects of tetrahydrobiopterin on adult individuals with phenylketonuria with measurable maladaptive behaviors.

    PubMed

    Moseley, Kathryn D; Ottina, Martha J; Azen, Colleen G; Yano, Shoji

    2015-04-01

    To evaluate the effects of tetrahydrobiopterin (BH4) on maladaptive behavior in patients with phenylketonuria (PKU). In an effort to determine if BH4 has any effects on the central nervous system, we studied 10 individuals with PKU and measurable maladaptive behaviors for 1 year. Behavioral assessments using the Vineland Adaptive Behavior Scales-Second Edition and a PKU Behavior Checklist were obtained at baseline, 6 months, and at the end of the study. Biochemical measures including plasma amino acids were obtained quarterly, and phenylalanine (Phe) and tyrosine (Tyr) were obtained monthly. Out of the 10 subjects, 2 were responders to BH4, as determined by a blood Phe reduction >30%. While blood Phe in the 8 nonresponders did not change significantly throughout the study, their Tyr levels were significantly higher at 6 months (p=0.012), but not at 12 months (p=0.23). By the end of the study, 8 subjects exhibited fewer maladaptive behaviors on the components of the Vineland Maladaptive Behavior Index, and all 10 had lower total scores on the PKU Behavior Checklist. These findings suggest that there may be direct effects of BH4 on the central nervous system, independent of lowering blood Phe.

  18. Unrestricted consumption of fruits and vegetables in phenylketonuria: no major impact on metabolic control.

    PubMed

    Rohde, C; Mütze, U; Weigel, J F W; Ceglarek, U; Thiery, J; Kiess, W; Beblo, S

    2012-05-01

    The treatment of phenylketonuria (PKU) requires consistent restriction of protein intake from natural sources. Therefore, protein from all foods has to be accounted for, even the small amounts in fruits and vegetables. We studied whether free consumption of fruits and vegetables containing less than 75 mg phenylalanine (phe) per 100 g affects metabolic control in children with PKU. Fourteen children (2-10 years) were included in a cross-over study, with a two-week period of conventional treatment (accounting for protein from fruits and vegetables) and a two-week period with free fruit and vegetable consumption. The instruction to follow liberal fruit and vegetable consumption in the first or second study period was randomized. Detailed daily dietary records were obtained throughout the study. Phe and nutrient content was calculated. Dried-blood phe concentration was monitored daily. Although total phe intake increased by an average of 58 mg per day (P=0.037) during the 2 weeks of free fruit and vegetable consumption, dried-blood phe concentrations were unchanged. Total intake of fruits and vegetables did not increase, but patients instead used the higher phe tolerance to consume more of other foods, which were calculated and accounted for. Free consumption of fruits and vegetables does not impair metabolic control in PKU patients over a 2-week period.

  19. Variability in phenylalanine control predicts IQ and executive abilities in children with phenylketonuria.

    PubMed

    Hood, Anna; Grange, Dorothy K; Christ, Shawn E; Steiner, Robert; White, Desirée A

    2014-04-01

    A number of studies have revealed significant relationships between cognitive performance and average phenylalanine (Phe) levels in children with phenylketonuria (PKU), but only a few studies have been conducted to examine the relationships between cognitive performance and variability (fluctuations) in Phe levels. In the current study, we examined a variety of indices of Phe control to determine which index best predicted IQ and executive abilities in 47 school-age children with early- and continuously-treated PKU. Indices of Phe control were mean Phe, the index of dietary control, change in Phe with age, and several indices of variability in Phe (standard deviation, standard error of estimate, and percentage of spikes). These indices were computed over the lifetime and during 3 developmental epochs (<5, 5.0-9.9, and ≥10 years of age). Results indicated that variability in Phe was generally a stronger predictor of cognitive performance than other indices of Phe control. In addition, executive performance was better predicted by variability in Phe during older than younger developmental epochs. These results indicate that variability in Phe should be carefully controlled to maximize cognitive outcomes and that Phe control should not be liberalized as children with PKU age. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Fluctuations in phenylalanine concentrations in phenylketonuria: a review of possible relationships with outcomes.

    PubMed

    Cleary, Maureen; Trefz, Friedrich; Muntau, Ania C; Feillet, François; van Spronsen, Francjan J; Burlina, Alberto; Bélanger-Quintana, Amaya; Giżewska, Maria; Gasteyger, Christoph; Bettiol, Esther; Blau, Nenad; MacDonald, Anita

    2013-12-01

    Fluctuations in blood phenylalanine concentrations may be an important determinant of intellectual outcome in patients with early and continuously treated phenylketonuria (PKU). This review evaluates the studies on phenylalanine fluctuations, factors affecting fluctuations, and if stabilizing phenylalanine concentrations affects outcomes, particularly neurocognitive outcome. Electronic literature searches of Embase and PubMed were performed for English-language publications, and the bibliographies of identified publications were also searched. In patients with PKU, phenylalanine concentrations are highest in the morning. Factors that can affect phenylalanine fluctuations include age, diet, timing and dosing of protein substitute and energy intake, dietary adherence, phenylalanine hydroxylase genotype, changes in dietary phenylalanine intake and protein metabolism, illness, and growth rate. Even distribution of phenylalanine-free protein substitute intake throughout 24h may reduce blood phenylalanine fluctuations. Patients responsive to and treated with 6R-tetrahydrobiopterin seem to have less fluctuation in their blood phenylalanine concentrations than controls. An increase in blood phenylalanine concentration may result in increased brain and cerebrospinal fluid phenylalanine concentrations within hours. Although some evidence suggests that stabilization of blood phenylalanine concentrations may have benefits in patients with PKU, more studies are needed to distinguish the effects of blood phenylalanine fluctuations from those of poor metabolic control. © 2013.

  1. Prooxidant-antioxidant balance in patients with phenylketonuria and its correlation to biochemical and hematological parameters.

    PubMed

    Tavana, Somayeh; Amini, Sabrieh; Hakhamaneshi, Mohammad Saeed; Andalibi, Pedram; Hajir, Mohammd Saleh; Ardalan, Azin; Abdi, Mohammad; Fathollahpour, Asadollah

    2016-06-01

    The balance between reactive oxygen species production and antioxidant activity has an important role in oxidative stress associated diseases such as phenylketonuria (PKU). We aimed in this study to evaluate the possible association between oxidative balance and clinical features of PKU patients. Twenty patients and 50 healthy subjects were selected. Prooxidant-antioxidant balance (PAB) was measured and phenylalanine (Phe), tyrosine (Tyr), Phe/Tyr ratio and hematological indices were determined. A significantly higher PAB value was observed in the patient group (152.0±14.1 HK unit) compared to the controls (88.1±13.88 HK) (p<0.05). There was significant correlation between PAB with serum Phe, Tyr, Phe/Tyr ratio, white blood cells (WBC) and red blood cells (RBC) counts. The serum PAB values were higher in patients with PKU and this was associated with the serum Phe and Tyr and Phe/Tyr ratio. Therefore, because of its low cost and simplicity to perform, PAB value might be considered as a useful monitoring marker among the other tools in these patients.

  2. Variability in Phenylalanine Control Predicts IQ and Executive Abilities in Children with Phenylketonuria

    PubMed Central

    Hood, Anna; Grange, Dorothy K.; Christ, Shawn E.; Steiner, Robert; White, Desirée A.

    2014-01-01

    A number of studies have revealed significant relationships between cognitive performance and average phenylalanine (Phe) levels in children with phenylketonuria (PKU), but only a few studies have been conducted to examine relationships between cognitive performance and variability (fluctuations) in Phe levels. In the current study, we examined a variety of indices of Phe control to determine which index best predicted IQ and executive abilities in 47 school-age children with early- and continuously-treated PKU. Indices of Phe control were mean Phe, the index of dietary control, change in Phe with age, and several indices of variability in Phe (standard deviation, standard error of estimate, and percentage of spikes). These indices were computed over the lifetime and during 3 developmental epochs (< 5, 5.0 – 9.9, and ≥ 10 yrs. of age). Results indicated that variability in Phe was generally a stronger predictor of cognitive performance than other indices of Phe control. In addition, executive performance was better predicted by variability in Phe during older than younger developmental epochs. These results indicate that variability in Phe should be carefully controlled to maximize cognitive outcomes, and that Phe control should not be liberalized as children with PKU age. PMID:24568837

  3. Assessment of the impact of phenylketonuria and its treatment on quality of life of patients and parents from seven European countries.

    PubMed

    Bosch, Annet M; Burlina, Alberto; Cunningham, Amy; Bettiol, Esther; Moreau-Stucker, Flavie; Koledova, Ekaterina; Benmedjahed, Khadra; Regnault, Antoine

    2015-06-18

    The strict and demanding dietary treatment and mild cognitive abnormalities seen in PKU treated from a young age can be expected to affect the health-related quality of life (HRQoL) of patients and their families. Our aim was to describe the HRQoL of patients with PKU from a large international study, using generic HRQoL measures and an innovative PKU-specific HRQoL questionnaire (PKU-QOL). Analyses were exploratory, performed post-hoc on data collected primarily to validate the PKU-QOL. A multicentre, prospective, non-interventional, observational study conducted in France, Germany, Italy, The Netherlands, Spain, Turkey and the UK. Patients diagnosed with PKU aged ≥9 years old and treated with a Phe-restricted diet and/or Phe-free amino acid protein supplements and/or pharmacological therapy were included in the study; parents of at least one patient with PKU aged <18 years were also included. HRQoL was assessed by generic measures (Pediatric Quality-of-Life Inventory; Medical Outcome Survey 36 item Short Form; Child Health Questionnaire 28 item Parent Form) and the newly developed PKU-QOL. Mean generic domain scores were interpreted using published reference values from the general population. PKU-QOL domain scores were described overall and in different subgroups of patients defined according to severity of PKU, overall assessment of patient's health status by the investigator and treatment with tetrahydrobiopterin (BH4). Data from 559 subjects were analysed: 306 patients (92 children, 110 adolescents, 104 adults) and 253 parents. Mean domain scores of generic measures in the study were comparable to the general population. The highest PKU-QOL impact scores (indicating greater impact) were for emotional impact of PKU, anxiety about blood Phe levels, guilt regarding poor adherence to dietary restrictions or Phe-free amino acid supplement intake and anxiety regarding blood Phe levels during pregnancy. Patients with mild/moderate PKU and those receiving BH4

  4. Glycomacropeptide, a low-phenylalanine protein isolated from cheese whey, supports growth and attenuates metabolic stress in the murine model of phenylketonuria

    PubMed Central

    Solverson, Patrick; Murali, Sangita G.; Brinkman, Adam S.; Nelson, David W.; Clayton, Murray K.; Yen, Chi-Liang Eric

    2012-01-01

    Phenylketonuria (PKU) is caused by a mutation in the phenylalanine (phe) hydroxylase gene and requires a low-phe diet plus amino acid (AA) formula to prevent cognitive impairment. Glycomacropeptide (GMP) contains minimal phe and provides a palatable alternative to AA formula. Our objective was to compare growth, body composition, and energy balance in Pahenu2 (PKU) and wild-type mice fed low-phe GMP, low-phe AA, or high-phe casein diets from 3–23 wk of age. The 2 × 2 × 3 design included main effects of genotype, sex, and diet. Fat and lean mass were assessed by dual-energy X-ray absorptiometry, and acute energy balance was assessed by indirect calorimetry. PKU mice showed growth and lean mass similar to wild-type littermates fed the GMP or AA diets; however, they exhibited a 3–15% increase in energy expenditure, as reflected in oxygen consumption, and a 3–30% increase in food intake. The GMP diet significantly reduced energy expenditure, food intake, and plasma phe concentration in PKU mice compared with the casein diet. The high-phe casein diet or the low-phe AA diet induced metabolic stress in PKU mice, as reflected in increased energy expenditure and intake of food and water, increased renal and spleen mass, and elevated plasma cytokine concentrations consistent with systemic inflammation. The low-phe GMP diet significantly attenuated these adverse effects. Moreover, total fat mass, %body fat, and the respiratory exchange ratio (CO2 produced/O2 consumed) were significantly lower in PKU mice fed GMP compared with AA diets. In summary, GMP provides a physiological source of low-phe dietary protein that promotes growth and attenuates the metabolic stress induced by a high-phe casein or low-phe AA diet in PKU mice. PMID:22297302

  5. Glycomacropeptide, a low-phenylalanine protein isolated from cheese whey, supports growth and attenuates metabolic stress in the murine model of phenylketonuria.

    PubMed

    Solverson, Patrick; Murali, Sangita G; Brinkman, Adam S; Nelson, David W; Clayton, Murray K; Yen, Chi-Liang Eric; Ney, Denise M

    2012-04-01

    Phenylketonuria (PKU) is caused by a mutation in the phenylalanine (phe) hydroxylase gene and requires a low-phe diet plus amino acid (AA) formula to prevent cognitive impairment. Glycomacropeptide (GMP) contains minimal phe and provides a palatable alternative to AA formula. Our objective was to compare growth, body composition, and energy balance in Pah(enu2) (PKU) and wild-type mice fed low-phe GMP, low-phe AA, or high-phe casein diets from 3-23 wk of age. The 2 × 2 × 3 design included main effects of genotype, sex, and diet. Fat and lean mass were assessed by dual-energy X-ray absorptiometry, and acute energy balance was assessed by indirect calorimetry. PKU mice showed growth and lean mass similar to wild-type littermates fed the GMP or AA diets; however, they exhibited a 3-15% increase in energy expenditure, as reflected in oxygen consumption, and a 3-30% increase in food intake. The GMP diet significantly reduced energy expenditure, food intake, and plasma phe concentration in PKU mice compared with the casein diet. The high-phe casein diet or the low-phe AA diet induced metabolic stress in PKU mice, as reflected in increased energy expenditure and intake of food and water, increased renal and spleen mass, and elevated plasma cytokine concentrations consistent with systemic inflammation. The low-phe GMP diet significantly attenuated these adverse effects. Moreover, total fat mass, %body fat, and the respiratory exchange ratio (CO(2) produced/O(2) consumed) were significantly lower in PKU mice fed GMP compared with AA diets. In summary, GMP provides a physiological source of low-phe dietary protein that promotes growth and attenuates the metabolic stress induced by a high-phe casein or low-phe AA diet in PKU mice.

  6. Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria.

    PubMed

    Aldámiz-Echevarría, Luis; Llarena, Marta; Bueno, María A; Dalmau, Jaime; Vitoria, Isidro; Fernández-Marmiesse, Ana; Andrade, Fernando; Blasco, Javier; Alcalde, Carlos; Gil, David; García, María C; González-Lamuño, Domingo; Ruiz, Mónica; Ruiz, María A; Peña-Quintana, Luis; González, David; Sánchez-Valverde, Felix; Desviat, Lourdes R; Pérez, Belen; Couce, María L

    2016-08-01

    Phenylketonuria (PKU), the most common inborn error of amino acid metabolism, is caused by mutations in the phenylalanine-4-hydroxylase (PAH) gene. This study aimed to assess the genotype-phenotype correlation in the PKU Spanish population and the usefulness in establishing genotype-based predictions of BH4 responsiveness in our population. It involved the molecular characterization of 411 Spanish PKU patients: mild hyperphenylalaninemia non-treated (mild HPA-NT) (34%), mild HPA (8.8%), mild-moderate (20.7%) and classic (36.5%) PKU. BH4 responsiveness was evaluated using a 6R-BH4 loading test. We assessed genotype-phenotype associations and genotype-BH4 responsiveness in our population according to literature and classification of the mutations. The mutational spectrum analysis showed 116 distinct mutations, most missense (70.7%) and located in the catalytic domain (62.9%). The most prevalent mutations were c.1066-11G>A (9.7%), p.Val388Met (6.6%) and p.Arg261Gln (6.3%). Three novel mutations (c.61-13del9, p.Ile283Val and p.Gly148Val) were reported. Although good genotype-phenotype correlation was observed, there was no exact correlation for some genotypes. Among the patients monitored for the 6R-BH4 loading test: 102 were responders (87, carried either one or two BH4-responsive alleles) and 194 non-responders (50, had two non-responsive mutations). More discrepancies were observed in non-responders. Our data reveal a great genetic heterogeneity in our population. Genotype is quite a good predictor of phenotype and BH4 responsiveness, which is relevant for patient management, treatment and follow-up.

  7. Improved nutritional management of phenylketonuria by using a diet containing glycomacropeptide compared with amino acids

    PubMed Central

    van Calcar, Sandra C; MacLeod, Erin L; Gleason, Sally T; Etzel, Mark R; Clayton, Murray K; Wolff, Jon A; Ney, Denise M

    2009-01-01

    Background: Phenylketonuria (PKU) requires a lifelong low-phenylalanine diet that provides the majority of protein from a phenylalanine-free amino acid (AA) formula. Glycomacropeptide (GMP), an intact protein formed during cheese production, contains minimal phenylalanine. Objective: The objective was to investigate the effects of substituting GMP food products for the AA formula on acceptability, safety, plasma AA concentrations, and measures of protein utilization in subjects with PKU. Design: Eleven subjects participated in an inpatient metabolic study with two 4-d treatments: a current AA diet (AA diet) followed by a diet that replaced the AA formula with GMP (GMP diet) supplemented with limiting AAs. Plasma concentrations of AAs, blood chemistries, and insulin were measured and compared in AA (day 4) and GMP diets (day 8). Results: The GMP diet was preferred to the AA diet in 10 of 11 subjects with PKU, and there were no adverse reactions to GMP. There was no significant difference in phenylalanine concentration in postprandial plasma with the GMP diet compared with the AA diet. When comparing fasting with postprandial plasma, plasma phenalyalanine concentration increased significantly with the AA but not with the GMP diet. Blood urea nitrogen was significantly lower, which suggests decreased ureagenesis, and plasma insulin was higher with the GMP diet than with the AA diet. Conclusions: GMP, when supplemented with limiting AAs, is a safe and highly acceptable alternative to synthetic AAs as the primary protein source in the nutritional management of PKU. As an intact protein source, GMP improves protein retention and phenylalanine utilization compared with AAs. PMID:19244369

  8. Adherence to clinic recommendations among patients with phenylketonuria in the United States.

    PubMed

    Jurecki, E R; Cederbaum, S; Kopesky, J; Perry, K; Rohr, F; Sanchez-Valle, A; Viau, K S; Sheinin, M Y; Cohen-Pfeffer, J L

    2017-03-01

    Assess current management practices of phenylketonuria (PKU) clinics across the United States (US) based on the key treatment metrics of blood phenylalanine (Phe) concentrations and blood Phe testing frequency, as well as patient adherence to their clinic's management practice recommendations. An online survey was conducted with medical professionals from PKU clinics across the US from July to September 2015. Forty-four clinics participated in the survey and account for approximately half of PKU patients currently followed in clinics in the US (Berry et al., 2013). The majority of PKU clinics recommended target blood Phe concentrations to be between 120 and 360μM for all patients; the upper threshold was relaxed by some clinics for adult patients (from 360 to 600μM) and tightened for patients who are pregnant/planning to become pregnant (to 240μM). Patient adherence to these recommendations (percentage of patients with blood Phe below the upper recommended threshold) was age-dependent, decreasing from 88% in the 0-4years age group to 33% in adults 30+ years. Patient adherence to recommendations for blood testing frequency followed a similar trend. Higher staffing intensity (specialists per 100 PKU patients) was associated with better patient adherence to clinics' blood Phe concentrations recommendations. Clinic recommendations of target blood Phe concentrations in the US are now stricter compared to prior years, and largely reflect recent guidelines by the American College of Medical Genetics and Genomics (Vockley et al., 2014). Adherence to recommended Phe concentrations remains suboptimal, especially in older patients. However, despite remaining above the guidelines, actual blood Phe concentrations in adolescents and adults are lower than those reported in the past (Walter et al., 2002; Freehauf et al., 2013). Continued education and support for PKU patients by healthcare professionals, including adequate clinic staffing, are needed to improve adherence

  9. Long-term follow-up of patients with phenylketonuria treated with tetrahydrobiopterin: a seven years experience.

    PubMed

    Scala, Iris; Concolino, Daniela; Della Casa, Roberto; Nastasi, Anna; Ungaro, Carla; Paladino, Serena; Capaldo, Brunella; Ruoppolo, Margherita; Daniele, Aurora; Bonapace, Giuseppe; Strisciuglio, Pietro; Parenti, Giancarlo; Andria, Generoso

    2015-02-08

    Phenylketonuria (PKU) is an autosomal recessive disorder caused by the deficiency of phenylalanine hydroxylase that catalyzes the conversion of phenylalanine to tyrosine, using tetrahydrobiopterin (BH4) as coenzyme. Besides dietary phenylalanine restriction, new therapeutic options are emerging, such as the treatment with BH4 in subgroups of PKU patients responding to a loading test with BH4. A no-profit open-label interventional trial with long-term oral BH4 therapy, sponsored by the Italian Medicines Agency (AIFA), was performed in a group of 17 PKU patients resulted as BH4 responders among 46 subjects analyzed for BH4-responsiveness (prot. FARM5MATC7). We report on efficacy and safety data of BH4 therapy and analyze factors predicting BH4-responsiveness and long-term response to BH4. A BH4-withdrawal test was used as a proof of the efficacy of long-term therapy with BH4. Forty-four percent of the patients responded to the 48 h-long loading test with BH4. All the phenotypic classes were represented. Genotype was the best predictor of responsiveness, along with lower phenylalanine levels at diagnosis, higher tolerance and lower phenylalanine/tyrosine ratio before the test. In BH4 responder patients, long-term BH4 therapy resulted safe and effective in increasing tolerance while maintaining a good metabolic control. The BH4 withdrawal test, performed in a subset of patients, showed that improved tolerance was directly dependent on BH4 assumption. Tolerance to phenylalanine was re-evaluated in 43.5% of patients and was longitudinally analyzed in 5 patients. Long-term treatment with BH4 is safe and effective in increasing tolerance to phenylalanine. There is real need to assess the actual tolerance to phenylalanine in PKU patients to ameliorate quality of life, improve nutritional status, avoiding unnecessarily restricted diets, and interpret the effects of new therapies for PKU.

  10. Evaluation of Neuropsychiatric Function in Phenylketonuria: Psychometric Properties of the ADHD Rating Scale-IV and Adult ADHD Self-Report Scale Inattention Subscale in Phenylketonuria.

    PubMed

    Wyrwich, Kathleen W; Auguste, Priscilla; Yu, Ren; Zhang, Charlie; Dewees, Benjamin; Winslow, Barbara; Yu, Shui; Merilainen, Markus; Prasad, Suyash

    2015-06-01

    Previous qualitative research among adults and parents of children with phenylketonuria (PKU) has identified inattention as an important psychiatric aspect of this condition. The parent-reported ADHD Rating Scale-IV (ADHD RS-IV) and the Adult ADHD Self-Report Scale (ASRS) have been validated for measuring inattention symptoms in persons with attention-deficit/hyperactivity disorder (ADHD); however, their psychometric attributes for measuring PKU-related inattention have not been established. The primary objective of this investigation was to demonstrate the reliability, validity, and responsiveness of the ADHD RS-IV and ASRS inattention symptoms subscales in a randomized controlled trial of patients with PKU aged 8 years or older. A post hoc analysis investigated the psychometric properties (Rasch model fit, reliability, construct validity, and responsiveness) of the ADHD RS-IV and ASRS inattention subscales using data from a phase 3b, double-blind, placebo-controlled clinical trial in those with PKU aged 8 years or older. The Rasch results revealed good model fit, and reliability analyses revealed strong internal consistency reliability (α ≥ 0.87) and reproducibility (intraclass correlation coefficient ≥ 0.87) for both measures. Both inattention measures demonstrated the ability to discriminate between known groups (P < 0.001) created by the Clinical Global Impression-Severity scale. Correlations between the ADHD RS-IV and the ASRS with the Clinical Global Impression-Severity scale and the age-appropriate Behavior Rating Inventory of Executive Function Working Memory subscale were consistently moderate to strong (r ≥ 0.56). Similarly, results of the change score correlations were of moderate magnitude (r ≥ 0.43) for both measures when compared with changes over time in Behavior Rating Inventory of Executive Function Working Memory subscales. These findings of reliability, validity, and responsiveness of both the ADHD RS-IV and the ASRS inattention scales

  11. Shape analysis of corpus callosum in phenylketonuria using a new 3D correspondence algorithm

    NASA Astrophysics Data System (ADS)

    He, Qing; Christ, Shawn E.; Karsch, Kevin; Peck, Dawn; Duan, Ye

    2010-03-01

    Statistical shape analysis of brain structures has gained increasing interest from neuroimaging community because it can precisely locate shape differences between healthy and pathological structures. The most difficult and crucial problem is establishing shape correspondence among individual 3D shapes. This paper proposes a new algorithm for 3D shape correspondence. A set of landmarks are sampled on a template shape, and initial correspondence is established between the template and the target shape based on the similarity of locations and normal directions. The landmarks on the target are then refined by iterative thin plate spline. The algorithm is simple and fast, and no spherical mapping is needed. We apply our method to the statistical shape analysis of the corpus callosum (CC) in phenylketonuria (PKU), and significant local shape differences between the patients and the controls are found in the most anterior and posterior aspects of the corpus callosum.

  12. Whole body composition analysis by the BodPod air-displacement plethysmography method in children with phenylketonuria shows a higher body fat percentage.

    PubMed

    Albersen, Monique; Bonthuis, Marjolein; de Roos, Nicole M; van den Hurk, Dorine A M; Carbasius Weber, Ems; Hendriks, Margriet M W B; de Sain-van der Velden, Monique G M; de Koning, Tom J; Visser, Gepke

    2010-12-01

    Phenylketonuria (PKU) causes irreversible central nervous system damage unless a phenylalanine (PHE) restricted diet with amino acid supplementation is maintained. To prevent growth retardation, a protein/amino acid intake beyond the recommended dietary protein allowance is mandatory. However, data regarding disease and/or diet related changes in body composition are inconclusive and retarded growth and/or adiposity is still reported. The BodPod whole body air-displacement plethysmography method is a fast, safe and accurate technique to measure body composition. To gain more insight into the body composition of children with PKU. Patients diagnosed with PKU born between 1991 and 2001 were included. Patients were identified by neonatal screening and treated in our centre. Body composition was measured using the BodPod system (Life Measurement Incorporation©). Blood PHE values determined every 1-3 months in the year preceding BodPod analysis were collected. Patients were matched for gender and age with data of healthy control subjects. Independent samples t tests, Mann-Whitney and linear regression were used for statistical analysis. The mean body fat percentage in patients with PKU (n = 20) was significantly higher compared to healthy controls (n = 20) (25.2% vs 18.4%; p = 0.002), especially in girls above 11 years of age (30.1% vs 21.5%; p = 0.027). Body fat percentage increased with rising body weight in patients with PKU only (R = 0.693, p = 0.001), but did not correlate with mean blood PHE level (R = 0.079, p = 0.740). Our data show a higher body fat percentage in patients with PKU, especially in girls above 11 years of age.

  13. Phenylketonuria is not a risk factor for changes of inflammation status as assessed by interleukin 6 and interleukin 8 concentrations.

    PubMed

    Mozrzymas, Renata; Duś-Żuchowska, Monika; Kałużny, Łukasz; Wenska-Chyży, Ewa; Walkowiak, Jarosław

    2016-01-01

    High oxidative stress and a reduced potential for free radical scavenging in phenylketonuria (PKU) patients, a phenomenon confirmed in a few studies, may lead to systemic chronic inflammation. The aim of this study was to compare the inflammation status, as assessed by interleukin 6 and interleukin 8 concentrations, in patients with PKU and in healthy controls. Twenty patients with classical PKU, aged 18-34 years and under dietary control, were enrolled in the study. The control group comprised of 20 healthy subjects matched for age and sex. Interleukin 6 and 8 levels were measured by enzyme-linked immunosorbent assay (ELISA) kits in all study participants. IL-6 concentrations in the study group ranged from 0.74 pg/ml to 1.34 pg/ml. No significant differences were found between IL-6 concentration between the study group and the control group (p = 0.989). IL-8 concentrations ranged from 17.56 pg/ml to 20.87 pg/ml. The obtained results of IL-8 levels did not differ significantly between the study group and control group (p = 0.192). No significant correlation was observed between Phe blood levels and IL-6 or IL-8 concentrations in the study group (ρ respectively: -0.225, 0.177). In a multivariate analysis, neither IL-6 nor IL-8 concentrations were correlated with sex, age, BMI and Phe levels. Phenylketonuria is not a risk factor for changes of inflammation status as assessed by IL-6 and IL-8 concentrations.

  14. Serum prolactin as a biomarker for the study of intracerebral dopamine effect in adult patients with phenylketonuria: a cross-sectional monocentric study.

    PubMed

    Juhász, Eszter; Kiss, Erika; Simonova, Erika; Patócs, Attila; Reismann, Peter

    2016-05-11

    It has been previously postulated that high phenylalanine (Phe) might disturb intracerebral dopamine production, which is the main regulator of prolactin secretion in the pituitary gland. Previously, various associations between Phe and hyperprolactinemia were revealed in studies performed in phenylketonuria (PKU) children and adolescents. The aim of the present study was to clarify whether any relation between serum phenylalanine and prolactin levels can be found in adult PKU patients. We conducted a cross-sectional, monocentric study including 158 adult patients (male n = 68, female n = 90) with PKU. All patients were diagnosed during newborn screening and were treated since birth. Serum Phe, tyrosine (Tyr), prolactin (PRL), and thyroid-stimulating hormone (TSH) levels were measured, and Phe/Tyr ratio was calculated. Males and females were analyzed separately because the serum prolactin level is gender-dependent. No significant correlations were found between serum phenylalanine, tyrosine, or the Phe/Tyr ratio and serum prolactin level either in the male or in the female group. In treated adult PKU patients, the serum prolactin level may not be significantly influenced by Phe or Tyr serum levels.

  15. [Screening for congenital hypothyroidism, phenylketonuria, galactosemia and biotinidase deficiency in a sample of mentally retarded patients in the city of Havana].

    PubMed

    Marrero-González, N; Portuondo-Sao, M; Lardoeyt-Ferrer, R; Tassé-Vila, D; Lantigua-Cruz, A

    Congenital hypothyroidism (CH), phenylketonuria (PKU), galactosemia (GAL) and biotinidase deficiency (BD) are innate errors in metabolism that share varying degrees of mental retardation (MR) as a common characteristic. AIMS. The aim of our study was to screen individuals with MR of unknown origin for CH, PKU, GAL and BD. Venous blood samples were collected on SS 903 specimen collection paper from 55 individuals with MR of unspecific origin born within the period 1977 1997. CH diagnosis was performed through determination of total thyroxine (T4) and thyroid stimulating hormone (TSH), using the UMELISA T4 and neonatal TSH reagent kits, respectively, and the detection of PKU, GAL and BD was conducted by determining phenylalanine (Phe), total galactose (Gal) and biotinidase enzyme activity (Biot) using UMTEST PKU, GAL and BIOTINIDASA. The mean values obtained for the analytes that were evaluated were: 0.8 mUI of TSH/L of total blood (EEM: 0.2), 113.1 nmol of T4/L of serum (EEM: 5.4), 67.7 mol of Phe/L of total blood (EEM: 0.1), 0.1 mmol of Gal/L of total blood (EEM: 0.01), and Biot activity was normal in all cases. This study enabled us to determine the T4, TSH, Phe and Gal levels in a sample from the Cuban population with MR of unknown causation. In addition, slightly higher levels of T4 were found in children who had hyperkinesis

  16. Developmental neurotoxicity: do similar phenotypes indicate a common mode of action? A comparison of fetal alcohol syndrome, toluene embryopathy and maternal phenylketonuria.

    PubMed

    Costa, L G; Guizzetti, M; Burry, M; Oberdoerster, J

    2002-02-28

    Developmental neurotoxicity can be ascribed to in utero exposure to exogenous substances or to exposure of the fetus to endogenous compounds that accumulate because of genetic mutations. One of the best recognized human neuroteratogens is ethanol. The Fetal Alcohol Syndrome (FAS) is characterized by growth deficiency, particular facial features, and central nervous system (CNS) dysfunctions (mental retardation, microencephaly and brain malformations). Abuse of toluene by pregnant women can lead to an embryopathy (fetal solvent syndrome, (FSS)) whose characteristics are similar to FAS. Phenylketonuria (PKU) is a genetic defect in phenylalanine (Phe) metabolism. Offspring of phenylketonuric mothers not under strict dietary control are born with maternal PKU (mPKU), a syndrome with similar characteristics as FAS and FSS. While ethanol has been shown to cause neuronal death, no such evidence is available for toluene or Phe and/or its metabolites. On the other hand, alterations in astrocyte proliferation and maturation have been found, mostly in in vitro studies, which may represent a potential common mode of action for at least some of the CNS effects found in FAS, mPKU, and FSS. Further in vivo and in vitro studies should validate this hypothesis and elucidate possible molecular targets.

  17. Tetrahydrobiopterin, its mode of action on phenylalanine hydroxylase, and importance of genotypes for pharmacological therapy of phenylketonuria.

    PubMed

    Heintz, Caroline; Cotton, Richard G H; Blau, Nenad

    2013-07-01

    In about 20%-30% of phenylketonuria (PKU) patients (all phenotypes of PAH deficiency), Phe levels may be controlled through phenylalanine hydroxylase cofactor tetrahydrobiopterin therapy. These patients can be diagnosed by an oral tetrahydrobiopterin challenge and are characterized by mutations coding for proteins with substantial residual PAH activity. They can be treated with a commercially available synthetic form of tetrahydrobiopterin, either as a monotherapy or as adjunct to the diet. This review article summarizes molecular and metabolic bases of PKU and the importance of the tetrahydrobiopterin loading test used for PKU patients. On the basis of in vitro residual PAH activity, more than 1,200 genotypes from patients challenged with tetrahydrobiopterin were categorized as predictive for tetrahydrobiopterin responsiveness or non-responsiveness and correlated with the loading test, phenotype, and residual in vitro PAH activity. The coexpression of two distinct PAH mutant alleles revealed possible dominance effects (positive or negative) by one of the mutations on residual activity as result of interallelic complementation. The treatment of the transfected cells with tetrahydrobiopterin showed an increase in residual PAH activity with several mutations coexpressed.

  18. A molecular survey of phenylketonuria in Iceland: identification of a founding mutation and evidence of predominant Norse settlement.

    PubMed

    Guldberg, P; Zschocke, J; Dagbjartsson, A; Henriksen, K F; Güttler, F

    1997-01-01

    Iceland was settled during the late 9th and early 10th centuries AD by Vikings who arrived from Norway and the British Isles. Although it is generally acknowledged that the Vikings brought with them Celtic slaves, the relative contribution of these peoples to the modern Icelandic gene pool has been a matter of considerable discussion. Most population genetic studies using classical markers have indicated a large Irish genetic contribution. We have investigated the molecular basis of phenylketonuria (PKU) in 17 Icelandic patients and found 9 different mutations in the phenylalanine hydroxylase gene. One novel mutation, Y377fsdelT, accounts for more than 40% of the mutant chromosomes. Haplotype data support a common ancestral origin of the mutation, and genealogical examination extending back more than 5 generations shows that this mutation has probably arisen in an isolated part of southern Iceland and was enriched by a founder effect. At least 7 PKU mutations have originated outside iceland. The almost exclusively Scandinavian background of these mutations and the complete absence of common Irish PKU mutations strongly support historical and linguistic evidence of a predominant Scandinavian heritage of the Icelandic people.

  19. The Enduring Behavioral Changes in Rats with Experimental Phenylketonuria*

    PubMed Central

    Andersen, Arnold E.; Rowe, Vernon; Guroff, Gordon

    1974-01-01

    The biochemical features of phenylketonuria have been reproduced in developing rat pups by administering to them a combination of p-chloro-DL-phenylalanine plus L-phenylalanine for the first 21 days after birth. During the treatment period, the experimental animals show delayed eye opening and decreased brain weight compared with controls given saline. Neuropathological examination of developing animals reveals deficient myelination and some inhibition of cerebellar maturation. When tested as adults, after a long recovery period, animals with phenylketonuria are hyperactive in activity wheels. Adult rats are deficient in reversing a position choice and demonstrate impaired performance in a Y-maze. Rats treated with p-chloro-DL-phenylalanine plus L-phenylalanine during the vulnerable period of rapid brain development thus have enduring behavioral changes that persist throughout life. Images PMID:4521053

  20. Role of nutrition in pregnancy with phenylketonuria and birth defects.

    PubMed

    Matalon, Kimberlee Michals; Acosta, Phyllis B; Azen, Colleen

    2003-12-01

    The maternal phenylketonuria (PKU) syndrome is caused by high blood phenylalanine (Phe) levels during pregnancy, leading to a host of birth defects, especially microcephaly and congenital heart disease (CHD). For finding whether the maternal PKU syndrome could be prevented, an international collaborative study was organized to evaluate treatment with a Phe-restricted diet. Blood Phe levels, maternal weight gain, and nutrient intakes during pregnancy were evaluated as to their effect on the rate of microcephaly and CHD in the offspring. The study was a prospective, longitudinal effort aimed at lowering blood Phe during pregnancy. Women were enrolled at time of referral for pregnancy. Nutrient intake analysis, which serves as the basis for this report, was available from 251 pregnancies. Subjects were stratified by blood Phe control of < or =600 micromol/L by 8 weeks gestation or >600 micromol/L by 8 weeks gestation. Outcome of these pregnancies was correlated to blood Phe levels, weight gain, and nutrient intake. The study goal was to attain blood Phe levels of 120 to 360 micromol/L 3 months preconception; however, this goal was achieved by only a limited number of patients. Therefore, the data presented were based on blood Phe control < or =600 micromol/L or >600 micromol/L by 8 weeks of gestation. Blood Phe control of < or =600 micromol/L by 8 weeks of gestation was attained by 86 (34.3%) of the 251 women in this study, whereas the other 165 women had blood Phe control >600 micromol/L by 8 weeks of gestation. Of the 251 offspring, 166 were born with normal head circumference and 85 were born with microcephaly (<2 standard deviations below normal). Women with blood Phe >600 micromol/L at 8 weeks of gestation included 78 (92%) of the 85 infants with microcephaly compared with 8% in the group of women who had blood Phe levels < or =600 micromol/L. Weight gain during pregnancy was related to the rate of microcephaly. The highest occurrence of microcephaly (58%) was

  1. A Comparison of Risperidone and Buspirone for Treatment of Behavior Disorders in Children with Phenylketonuria

    PubMed Central

    FAYYAZI, Afshin; SALARI, Elham; KHAJEH, Ali; GAJARPOUR, Abdi

    2014-01-01

    Objective Many patients with late-diagnosed phenylketonuria (PKU) suffer from severe behavior problems. This study compares the effects of buspirone and risperidone on reducing behavior disorders in these patients. Materials & Methods In this crossover clinical trial study, patients with severe behavior disorders after medical examination were randomly divided into two groups of two 8-week crossover treatments with risperidone or buspirone. Patient behavioral disorders before and after treatment by each drug was rated by parents on the Nisonger Child Behavior Rating Form (NCBRF), and after treatment by each drug, were assessed by a physician through clinical global impression (CGI). Results Thirteen patients were able to complete the therapy period with these two medications. The most common psychiatric diagnoses were intellectual disability accompanied by pervasive developmental disorder NOS, and intellectual disability accompanied by autistic disorder. Risperidone was significantly effective in reducing the NCBRF subscales of hyperactivity disruptive/stereotypic, and conduct problems. Treatment by buspirone only significantly decreased the severity of hyperactivity, but other behavior aspects showed no significant differences. Assessment of the severity of behavior disorder after treatment by risperidone and buspirone showed significant differences in reducing hyperactivity and masochistic/stereotype. Conclusion Although buspirone is effective in controlling hyperactivity in patients with PKU, it has no preference over risperidone. Therefore, it is recommended as an alternative to risperidone. PMID:25657768

  2. Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability.

    PubMed

    Gersting, Søren W; Kemter, Kristina F; Staudigl, Michael; Messing, Dunja D; Danecka, Marta K; Lagler, Florian B; Sommerhoff, Christian P; Roscher, Adelbert A; Muntau, Ania C

    2008-07-01

    A significant share of patients with phenylalanine hydroxylase (PAH) deficiency benefits from pharmacological doses of tetrahydrobiopterin (BH(4)), the natural PAH cofactor. Phenylketonuria (PKU) is hypothesized to be a conformational disease, with loss of function due to protein destabilization, and the restoration of enzyme function that is observed in BH(4) treatment might be transmitted by correction of protein misfolding. To elucidate the molecular basis of functional impairment in PAH deficiency, we investigated the impact of ten PAH gene mutations identified in patients with BH(4)-responsiveness on enzyme kinetics, stability, and conformation of the protein (F55L, I65S, H170Q, P275L, A300S, S310Y, P314S, R408W, Y414C, Y417H). Residual enzyme activity was generally high, but allostery was disturbed in almost all cases and pointed to altered protein conformation. This was confirmed by reduced proteolytic stability, impaired tetramer assembly or aggregation, increased hydrophobicity, and accelerated thermal unfolding--with particular impact on the regulatory domain--observed in most variants. Three-dimensional modeling revealed the involvement of functionally relevant amino acid networks that may communicate misfolding throughout the protein. Our results substantiate the view that PAH deficiency is a protein-misfolding disease in which global conformational changes hinder molecular motions essential for physiological enzyme function. Thus, PKU has evolved from a model of a genetic disease that leads to severe neurological impairment to a model of a treatable protein-folding disease with loss of function.

  3. Adjusting diet with sapropterin in phenylketonuria: what factors should be considered?

    PubMed

    MacDonald, Anita; Ahring, Kirsten; Dokoupil, Katharina; Gokmen-Ozel, Hulya; Lammardo, Anna Maria; Motzfeldt, Kristina; Robert, Martine; Rocha, Júlio César; van Rijn, Margreet; Bélanger-Quintana, Amaya

    2011-07-01

    The usual treatment for phenylketonuria (PKU) is a phenylalanine-restricted diet. Following this diet is challenging, and long-term adherence (and hence metabolic control) is commonly poor. Patients with PKU (usually, but not exclusively, with a relatively mild form of the disorder) who are responsive to treatment with pharmacological doses of tetrahydrobiopterin (BH4) have either lower concentrations of blood phenylalanine or improved dietary phenylalanine tolerance. The availability of a registered formulation of BH4 (sapropterin dihydrochloride, Kuvan®) has raised many practical issues and new questions in the dietary management of these patients. Initially, patients and carers must understand clearly the likely benefits (and limitations) of sapropterin therapy. A minority of patients who respond to sapropterin are able to discontinue the phenylalanine-restricted diet completely, while others are able to relax the diet to some extent. Care is required when altering the phenylalanine-restricted diet, as this may have unintended nutritional consequences and must be undertaken with caution. New clinical protocols are required for managing any dietary change while maintaining control of blood phenylalanine, ensuring adequate nutrition and preventing nutritional deficiencies, overweight or obesity. An accurate initial evaluation of pre-sapropterin phenylalanine tolerance is essential, and the desired outcome from treatment with sapropterin (e.g. reduction in blood phenylalanine or relaxation in diet) must also be understood by the patient and carers from the outset. Continuing education and support will be required thereafter, with further adjustment of diet and sapropterin dosage as a young patient grows.

  4. Correlation between genotype and the tetrahydrobiopterin-responsive phenotype in Chinese patients with phenylketonuria.

    PubMed

    Tao, Jing; Li, Nana; Jia, Haitao; Liu, Zhen; Li, Xiaohong; Song, Jiaping; Deng, Ying; Jin, Xi; Zhu, Jun

    2015-12-01

    A growing body of research has suggested that tetrahydrobiopterin (BH4) responsive phenotype can be predicted by the phenylalanine hydroxylase (PAH) genotype in patients with phenylketonuria (PKU), but data concerning the association between genotype and BH4 responsiveness are scarce in China. A total of 165 PKU patients from China who had undergone a 24-h loading test with BH4 administration were recruited. Genotyping was performed by the next-generation sequencing (NGS) technique. Using the predicted residual PAH activity, we analyzed the association between genotype and BH4-responsiveness. Among the 165 patients, 40 patients (24.24%) responded to BH4. A total of 74 distinct mutations were observed, including 13 novel mutations. The mutation p.R241C was most frequently associated with response. Two known mutations (p.A322T and p.Q419R) and two novel mutations (p.L98V and IVS3-2A>T) were first reported as responsive to BH4. Residual PAH activity of at least 12.5% was needed for responsive genotypes. Genotype-based predictions of BH4-responsiveness are only for selecting potential responders. Accordingly, it is necessary to test potential responders with a long-term BH4 challenge.

  5. Mutation profiles of phenylketonuria in Quebec populations: Evidence of stratification and novel mutations

    SciTech Connect

    Rozen, R.; Mascisch, A.; Scriver, C.R. ); Lambert, M. ); Laframboise, R. )

    1994-08-01

    Independent phenylketonuria (PKU) chromosomes (n=109) representing 80% of a proband cohort in Quebec province carry 18 different identified mutations in 20 different mutation/haplotype combinations. The study reported here, the third in a series on Quebec populations, was done in the Montreal region and predominantly on French Canadians. It has identified three novel mutations (A309D, D338Y, and 1054/1055delG [352fs]) and one unusual mutation/RFLP haplotype combination (E280K on Hp 2). The relative frequencies and distribution of PKU mutations were then compared in three regions and population subsets (eastern Quebec, French Canadian; western Quebec, French Canadian; and Montreal, non-French Canadian). The distributions of the prevalent and rare mutations are nonrandom and provide evidence for genetic stratification. The latter and the presence of eight unusual mutation/haplotype combinations in Quebec families with European ancestries (the aforementioned four and M1V, 165T, S349P, and R408W on Hp 1) corroborate demographic and anthropologic evidence, from elsewhere, for different origins of French Canadians in eastern and western Quebec. 29 refs., 1 fig., 1 tab.

  6. [Characteristics of phenylalanine hydroxylase gene mutations among patients with phenylketonuria from Linyi region of Shandong Province].

    PubMed

    Li, Huafeng; Li, Yongli; Zhang, Li

    2017-06-10

    To explore the characteristics of (PAH) gene mutations among patients with phenylketonuria (PKU) from Linyi area of Shandong Province. For 51 children affected with PKU and their parents, the 13 exons and their flanking intronic sequences of the PAH gene were directly sequenced with Sanger method. PAH gene mutations were detected in all of the 102 alleles of the patients, which included 31 types of mutations. Common mutations included R243Q (17/102, 16.67%), IVS4-1G to A (9/102, 8.82%), R241C (8/102, 7.84%), R111X (8/102, 7.84%), and V399V (8/102, 7.84%). In addition, two novel mutations, D101N, 345-347del, have been detected. The 31 types of mutations included missense, nonsense, deletion, and splicing mutations, which were mainly located in exons 7 (29, 28.43%), 11 (18, 17.65%), 3 (16, 15.69%) and 12 (13, 12.75%). Mutations of the PAH gene in Linyi region mainly distributed in exons 7, 11, and 3, and the most common mutation were R243Q. Two novel mutations, D101N and 345-347del, have been detected.

  7. Regional mapping of the phenylalanine hydroxylase gene and the phenylketonuria locus in the human genome

    SciTech Connect

    Lidsky, A.S.; Law, M.L.; Morse, H.G.; Kao, F.T.; Rabin, M.; Ruddle, F.H.; Woo, S.L.C.

    1985-09-01

    Phenylketonuria (PKU) is an autosomal recessive disorder of amino acid metabolism caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase. To define the regional map position of the disease locus and the PAH gene on human chromosome 12, DNA was isolated from human-hamster somatic cell hybrids with various deletions of human chromosome 12 and was analyzed by Southern blot analysis using the human cDNA PAH clone as a hybridization probe. From these results, together with detailed biochemical and cytogenetic characterization of the hybrid cells, the region on chromosome 12 containing the human PAH gene has been defined as 12q14.3..-->..qter. The PAH map position on chromosome 12 was further localized by in situ hybridization of /sup 125/I-labeled human PAH cDNA to chromosomes prepared from a human lymphoblastoid cell line. Results of these experiments demonstrated that the region on chromosome 12 containing the PAH gene and the PKU locus in man is 12q22..-->..12q24.1. These results not only provide a regionalized map position for a major human disease locus but also can serve as a reference point for linkage analysis with other DNA markers on human chromosome 12.

  8. Challenges of Implementation of the National Phenylketonuria Screening Program in Iran: A Qualitative Study

    PubMed Central

    Heidari, Alireza; Arab, Mohammad; Etemad, Koorosh; Damari, Behzad; Kabir, Mohammad Javad

    2016-01-01

    Introduction Newborn screening (NBS) is a public health measure aimed at identification of early cases, management of afflicted infants, and making efforts to reduce the morbidity and mortality among newborns. All countries may face challenges in implementation of screening programs. The present study aimed to determine the challenges of implementation of the National Phenylketonuria (PKU) Screening Program in Iran. Methods In this qualitative study, 38 health policymakers, managers, and PKU experts in Iran were purposively selected as the respondents in 2015. The semi-structured interview was used for collecting the required data and information. After transcription of interviews, their content was analyzed using framework analysis. Results The results were categorized into five main themes and 22 subthemes. The main themes extracted from data were management challenges, diagnosis challenges, treatment challenges, care challenges, and patients’ family problems. Each category consisted of several subthemes. Conclusion Considering the challenges of implementing this program, some measures such as increased stability of managers in the health system, greater interaction of the Ministry of Health and Medical Education with the heath stakeholders, improving the level of parents’ awareness, the use of efficient information systems, support and legal backing for requiring parents who refuse newborn screening for various reasons, and appropriate insurance coverage seem necessary to be taken. PMID:27957302

  9. Remarkable differences: the course of life of young adults with galactosaemia and PKU.

    PubMed

    Bosch, A M; Maurice-Stam, H; Wijburg, F A; Grootenhuis, M A

    2009-12-01

    Although the need for insight in factors influencing the quality of life of patients with an inborn error of metabolism is recognized, psychological adjustment of adults with metabolic diseases has not been properly studied. Adult patients with PKU were demonstrated not to differ from healthy controls in terms of their course of life (CoL) and health-related quality of life (HRQoL). However, adults with galactosaemia had a lower HRQoL with significant lower scores on the domains of cognitive and social function. This study investigated the CoL and the social demographical outcomes in these young adults with galactosaemia, and compared them with the general population and with PKU patients. A total of 15 (88%) adult patients with classical galactosaemia participated in this study. Classical galactosaemia patients had a delayed social and psychosexual development compared to their peers from the general population and to PKU patients. Also, they were significantly less frequently married or living together and significantly less frequently employed than the general population. Our study shows a stark contrast between patients with galactosaemia and patients with PKU, although both are diagnosed in the neonatal period and need life-long dietary restrictions. The observed difference is likely due to the long-term somatic complications frequently seen in galactosaemia and thus not due to the burden of a chronic disease necessitating life-long dietary restrictions. We conclude that it is essential that parents and clinicians encourage children with galactosaemia to participate in peer-related activities in order to stimulate social performance, which may result in a more normal CoL.

  10. Reassessment of Phenylalanine Tolerance in Adults with Phenylketonuria is Needed as Body Mass Changes

    PubMed Central

    MacLeod, Erin L.; Gleason, Sally T.; van Calcar, Sandra C.; Ney, Denise M.

    2009-01-01

    Lifelong treatment of phenylketonuria (PKU) includes a phenylalanine (phe) restricted diet that provides sufficient phe for growth and maintenance plus phe-free amino acid formula to meet requirements for protein, energy and micronutrients. Phe tolerance (mg phe/kg body weight/day) is the amount of phe those with PKU can consume and maintain acceptable blood phe levels; it requires individual assessment because of varying phenylalanine hydroxylase activity. The objective was to reassess phe tolerance in 8 adults with PKU considering phe requirements, blood phe levels, genotype and phe tolerance at 5 years of age. Subjects had not received a personalized assessment of phe tolerance in several years, and 5 subjects were overweight, body mass index (BMI) 25–28. With the guidance of a metabolic dietitian, 7 subjects increased phe tolerance (by 15–173%) without significantly increasing blood phe concentration. Increased phe tolerance was associated with both improved dietary compliance and inadequate phe intake at the onset of the protocol compared with current requirements. Improved dietary compliance reflected increased consumption of protein equivalents from amino acid formula and increased frequency of formula intake, from 2.2 to 3 times per day. Predictors of higher final phe tolerance following reassessment included being male and having a lower BMI (R2=0.588). This suggests that the rising trend of overweight and obesity may affect assessment of phe tolerance in adults. Therefore, interaction with the metabolic dietitian to reassess phe tolerance in relation to body mass is essential throughout adulthood to insure adequate intake of phe to support protein synthesis and prevent catabolism. PMID:19747868

  11. Special low protein foods for phenylketonuria: availability in Europe and an examination of their nutritional profile.

    PubMed

    Pena, Maria João; Almeida, Manuela Ferreira; van Dam, Esther; Ahring, Kirsten; Bélanger-Quintana, Amaya; Dokoupil, Katharina; Gokmen-Ozel, Hulya; Lammardo, Anna Maria; MacDonald, Anita; Robert, Martine; Rocha, Júlio César

    2015-12-22

    Special low protein foods (SLPF) are essential in the nutritional management of patients with phenylketonuria (PKU). The study objectives were to: 1) identify the number of SLPF available for use in eight European countries and Turkey and 2) analyse the nutritional composition of SLPF available in one of these countries. European Nutritionist Expert Panel on PKU (ENEP) members (Portugal, Spain, Belgium, Italy, Germany, Netherlands, UK, Denmark and Turkey) provided data on SPLF available in each country. The nutritional composition of Portuguese SLPF was compared with regular food products. The number of different SLPF available in each country varied widely with a median of 107 [ranging from 73 (Portugal) and 256 (Italy)]. Food analysis of SLPF available from a single country (Portugal) indicated that the mean phenylalanine content was higher in low protein baby cereals (mean 48 mg/100 g) and chocolate/energy bars/jelly (mean 41 mg/100 g). The energy content of different foods from a sub-group of SLPF (cookies) varied widely between 23 and 96 kcal/cookie. Low protein bread had a high fat content [mean 5.8 g/100 g (range 3.7 to 10)] compared with 1.6 g/100 g in regular bread. Seven of the 12 SLPF sub-groups (58 %) did not declare any vitamin content, and only 4 (33 %) identified a limited number of minerals. Whilst equal and free access to all SLPF is desirable, the widely variable nutritional composition requires careful nutritional knowledge of all products when prescribed for individual patients with PKU. There is a need for more specific nutritional standards for special low protein foods.

  12. A biochemical explanation of phenyl acetate neurotoxicity in experimental phenylketonuria.

    PubMed

    Loo, Y H; Potempska, A; Wisniewski, H M

    1985-11-01

    The in vivo formation of [1-14C]acetyl-coenzyme A from D-[3-14C]3-hydroxybutyrate in the brain of the suckling rat was not affected by postnatal exposure to phenyl acetate. However, utilization of the generated acetyl-coenzyme A was significantly inhibited in certain metabolic reactions, namely synthesis of fatty acids and of sterols, but not in others as the Krebs cycle reactions that lead to the production of dicarboxylic amino acids. The incorporation of D-[U-14C]glucosamine into N-acetylneuraminic acid bound to glycoproteins was appreciably diminished in the rat pup previously exposed to maternal phenylketonuria induced by phenyl acetate. During the period of very rapid development of the brain, interference by phenyl acetate and/or its metabolites with certain critical biosynthetic pathways that require acetyl-coenzyme A would significantly contribute to retarded maturation of the brain that occurs in phenylketonuria.

  13. Wechsler subscale IQ and subtest profile in early treated phenylketonuria

    PubMed Central

    Griffiths, P; Demellweek, C; Fay, N; Robinson, P; Davidson, D

    2000-01-01

    AIM—Mildly depressed IQ is common in treated phenylketonuria. This study explored whether a particular intellectual ability profile typifies early and continuously treated phenylketonuria and whether component skills comprising the IQ relate to socioeconomic and treatment factors.
METHODS—IQ scores were collected retrospectively from variants of the "Wechsler intelligence scale for children" performed at age 8 on 57 children with early treated, classic phenylketonuria. The mental ability pattern underlying IQ was investigated by analysing subscale and subtest scores and dietary factors, such as historical phenylalanine blood concentrations.
RESULTS—The children's mean full scale IQ of 91.11 was significantly below the healthy population norm. There was a significant discrepancy between their mean verbal IQ (94.65) and mean performance IQ (89.42), suggestive of a spatial deficit, but the data did not support a biochemical or sociological explanation. Individual Wechsler subtests had no distinctive pattern. Phenylalanine control at age 2 was predictive of overall IQ. At this age, children with annual median phenylalanine < 360 µmol/litre (recommended UK upper limit) had a mean IQ 10 points higher than those above.
CONCLUSIONS—Early and continuous treatment of phenylketonuria does not necessarily lead to normalisation of overall IQ. Verbal intelligence in the primary school years appears to normalise if blood phenylalanine is maintained below 360 µmol/litre in infancy, but spatial intelligence may remain poor. However, the discrepancy in skill development is not the result of social status or treatment variables. Perhaps weak spatial intelligence is an ancillary effect of a protective rearing style occasioned by the dietary treatment regimen.
 PMID:10685922

  14. An Objective Approach to Measurement of Interpersonal Behavior in Phenylketonuria

    ERIC Educational Resources Information Center

    Friedman, C. J.; And Others

    1971-01-01

    Among the findings were that PKU Children judged to be emotionally disturbed and inadequate in communication performed more poorly than those PKU children judged nondisturbed and more adequate in communication under two of the three social stimulus interaction condictions. (Author)

  15. An Objective Approach to Measurement of Interpersonal Behavior in Phenylketonuria

    ERIC Educational Resources Information Center

    Friedman, C. J.; And Others

    1971-01-01

    Among the findings were that PKU Children judged to be emotionally disturbed and inadequate in communication performed more poorly than those PKU children judged nondisturbed and more adequate in communication under two of the three social stimulus interaction condictions. (Author)

  16. The Electro-Encephalogram in Phenylketonuria

    ERIC Educational Resources Information Center

    Todd, Peter G.; Pitt, D. B.

    1973-01-01

    Evaluated were electroencephalographic findings in 24 untreated (ages from 4 to 38 years) patients suffereing from phenylketonuria (a metabolic disorder producing severe mental retardation if not treated with proper diet during the early years). (DB)

  17. The Electro-Encephalogram in Phenylketonuria

    ERIC Educational Resources Information Center

    Todd, Peter G.; Pitt, D. B.

    1973-01-01

    Evaluated were electroencephalographic findings in 24 untreated (ages from 4 to 38 years) patients suffereing from phenylketonuria (a metabolic disorder producing severe mental retardation if not treated with proper diet during the early years). (DB)

  18. Probabilistic modelling to assess exposure to three artificial sweeteners of young Irish patients aged 1-3 years with PKU and CMPA.

    PubMed

    O'Sullivan, Aaron J; Pigat, Sandrine; O'Mahony, Cian; Gibney, Michael J; McKevitt, Aideen I

    2016-11-01

    The choice of suitable normal foods is limited for individuals with particular medical conditions, e.g., inborn errors of metabolism (phenylketonuria - PKU) or severe cow's milk protein allergy (CMPA). Patients may have dietary restrictions and exclusive or partial replacement of specific food groups with specially formulated products to meet particular nutrition requirements. Artificial sweeteners are used to improve the appearance and palatability of such food products to avoid food refusal and ensure dietary adherence. Young children have a higher risk of exceeding acceptable daily intakes for additives than adults due to higher food intakes kg(-1) body weight. The Budget Method and EFSA's Food Additives Intake Model (FAIM) are not equipped to assess partial dietary replacement with special formulations as they are built on data from dietary surveys of consumers without special medical requirements impacting the diet. The aim of this study was to explore dietary exposure modelling as a means of estimating the intake of artificial sweeteners by young PKU and CMPA patients aged 1-3 years. An adapted validated probabilistic model (FACET) was used to assess patients' exposure to artificial sweeteners. Food consumption data were derived from the food consumption survey data of healthy young children in Ireland from the National Preschool and Nutrition Survey (NPNS, 2010-11). Specially formulated foods for special medical purposes were included in the exposure model to replace restricted foods. Inclusion was based on recommendations for adequate protein intake and dietary adherence data. Exposure assessment results indicated that young children with PKU and CMPA have higher relative average intakes of artificial sweeteners than healthy young children. The reliability and robustness of the model in the estimation of patient additive exposures was further investigated and provides the first exposure estimates for these special populations.

  19. Adults with late diagnosed PKU and severe challenging behaviour: a randomised placebo-controlled trial of a phenylalanine-restricted diet.

    PubMed

    Lee, P J; Amos, A; Robertson, L; Fitzgerald, B; Hoskin, R; Lilburn, M; Weetch, E; Murphy, G

    2009-06-01

    Although early diagnosis and treatment in phenylketonuria (PKU) leads to excellent outcomes, a population of adults born before the introduction of newborn screening exists. They can have severe intellectual disabilities and behavioural problems, and are often dependent on full-time carers. Anecdotal evidence suggests that a diet that lowers blood phenylalanine concentration can have significant benefits upon behaviour. A prospective double-blind randomised placebo-controlled crossover trial of phenylalanine-restricted diet was performed in a group of 34 adults (aged 21-61 years, median 49) with late diagnosed PKU with severe challenging behaviour. Only 17 completed the 60 week study: seven withdrew before the end of the baseline period; five withdrew during the first diet period; five withdrew during the second diet period (after moving into placebo phase). The mean (SD) blood phenylalanine was 1570 (222) micromol/l during baseline, 553(158) mumol/l during the active phase and 1444 (255) micromol/l during the placebo phase. In the 22 participants exposed to both active and placebo phases, no differences were demonstrated in behaviour assessed by the Aberrant Behavior Checklist and Vineland Adaptive Behavior Scales, behaviour diaries or on video analysis of direct observations. However, 76% of carers' comments were scored as positive during the active phase, compared with 54% during the placebo phase (chi(2) = 38.06, p<0.001). There are significant challenges in studying people with intellectual disabilities and considerable difficulties in instituting phenylalanine-restricted diet in this population. However, if attempted, there are potential benefits to quality of life for the individuals with PKU and their carers.

  20. [High plasma folate in patients with phenylketonuria].

    PubMed

    Zielińska, Magdalena; Żółkowska, Joanna; Przybylska-Kruszewska, Amanda; Gładysz, Dominika; Korycińska-Chaaban, Dorota; Nowacka, Maria; Hozyasz, Kamil K

    2016-04-01

    Phenylketonuria is an inborn error of metabolism treated with a closely monitored low phenylalanine diet. Protein substitutes used for treatment are supplemented with vitamins and micronutrients. The aim of this study was to investigate plasma folic acid concentrations in children with phenylketonuria. Retrospective analysis of medical records of 73 patients with phenylketonuria and 28 with mild hyperphenylalaninemia (on normal diet) was carried out. Intake of folic acid was calculated on the basis of protein substitute intake. Folate concentrations were analyzed according to their intake, and concentration of homocysteine and phenylalanine. In 76.7% patients with phenylketonuria intake of folic acid exceeded recommended dietary allowance. Serum folic acid concentrations above upper reference level were detected in 75.3% patients with phenylketonuria and only in 25% patients with hyperphenylalaninemia (p<0.0001). Strong positive correlation between daily intake of folic acid (with protein substitute) and concentration plasma folic acid (corr=0.55, p<0.0001) has been observed. Low phenylalanine diet using protein substitutes currently available in Poland predisposes to high concentration of plasma folic acid. The security of folic acid hipersupplementation in patients with phenylketonuria requires further detailed research. © 2016 MEDPRESS.

  1. Genetics Home Reference: phenylketonuria

    MedlinePlus

    ... up to harmful levels in the body, causing intellectual disability and other serious health problems. The signs and ... months old. Without treatment, these children develop permanent intellectual disability. Seizures, delayed development, behavioral problems, and psychiatric disorders ...

  2. Mutation frequency and genotype/phenotype correlation among phenylketonuria patients from Georgia

    SciTech Connect

    Woo, S.L.C.; Martinez, D.; Kuozmine, A.

    1994-09-01

    Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH). To determine the molecular basis of PKU in the state of Georgia, thirty-five Georgian PKU patients representing sixty independent alleles were examined by a combination of DGGE and direct sequence analysis. At present, this approach has led to the identification of 55/60 or about 92% of all mutant alleles. The relatively high frequencies of mutations common to the British Isles (R408W, I65T and L348V) are compatible with 1990 census data showing that 34% of the general Georgian population claim Irish, English or Scottish ancestors. Three new mutations, E76A (1/60), R241L (2/60), and R400R (2/60), were also detected in this study. Although the nucleotide substitution in codon 400 (AGG{r_arrow}CGG) did not change the amino acid sequence, it was the only base change detected in a scan of all 13 exons of two independent alleles. Since codon 400 is split between exons 11 and 12, this change may exert some effect on splicing, as has previously been seen in the PAH gene for the silent mutation Q304Q and the nonsense mutation Y356X, each of which effect codons immediately adjacent to splicing signals. This hypothesis remains to be tested by expression analysis or studies of ectopic transcripts. The remaining 19 characterized alleles contained one of 15 previously identified mutations. Twenty-five of the thirty non-related patients examined in this study were completely genotyped, and there was a strong correlation between mutant PAH genotype, PAH activity predicted from in vitro expression studies where known, and PKU or HPA phenotype. For mutations not yet studied by expression analysis, this correlation suggests that L213P, R241L, Y277D may drastically reduce residual PAH activity while F39L and E76A may retain significant amounts of PAH activity.

  3. Factors Influencing Verbal Intelligence and Spoken Language in Children with Phenylketonuria.

    PubMed

    Soleymani, Zahra; Keramati, Nasrin; Rohani, Farzaneh; Jalaei, Shohre

    2015-05-01

    To determine verbal intelligence and spoken language of children with phenylketonuria and to study the effect of age at diagnosis and phenylalanine plasma level on these abilities. Cross-sectional. Children with phenylketonuria were recruited from pediatric hospitals in 2012. Normal control subjects were recruited from kindergartens in Tehran. 30 phenylketonuria and 42 control subjects aged 4-6.5 years. Skills were compared between 3 phenylketonuria groups categorized by age at diagnosis/treatment, and between the phenylketonuria and control groups. Scores on Wechsler Preschool and Primary Scale of Intelligence for verbal and total intelligence, and Test of Language Development-Primary, third edition for spoken language, listening, speaking, semantics, syntax, and organization. The performance of control subjects was significantly better than that of early-treated subjects for all composite quotients from Test of Language Development and verbal intelligence (P<0.001). Early-treated subjects scored significantly higher than the two groups of late-treated subjects for spoken language (P=0.01), speaking (P=0.04), syntax (P=0.02), and verbal intelligence (P=0.019). There was a negative correlation between phenylalanine level and verbal intelligence (r=-0.79) in early-treated subjects and between phenylalanine level and spoken language (r=-0.71), organization (r=-0.82) and semantics (r=-0.82) for late-treated subjects diagnosed before the age one year. The study confirmed that diagnosis of newborns and control of blood phenylalanine concentration improves verbal intelligence and spoken language scores in phenylketonuria subjects.

  4. Intense beams from gases generated by a permanent magnet ECR ion source at PKU

    SciTech Connect

    Ren, H. T.; Chen, J. E.; Peng, S. X.; Lu, P. N.; Yan, S.; Zhou, Q. F.; Zhao, J.; Yuan, Z. X.; Guo, Z. Y.

    2012-02-15

    An electron cyclotron resonance (ECR) ion source is designed for the production of high-current ion beams of various gaseous elements. At the Peking University (PKU), the primary study is focused on developing suitable permanent magnet ECR ion sources (PMECRs) for separated function radio frequency quadrupole (SFRFQ) accelerator and for Peking University Neutron Imaging Facility. Recently, other kinds of high-intensity ion beams are required for new acceleration structure demonstration, simulation of fusion reactor material irradiation, aviation bearing modification, and other applications. So we expanded the ion beam category from O{sup +}, H{sup +}, and D{sup +} to N{sup +}, Ar{sup +}, and He{sup +}. Up to now, about 120 mA of H{sup +}, 83 mA of D{sup +}, 50 mA of O{sup +}, 63 mA of N{sup +}, 70 mA of Ar{sup +}, and 65 mA of He{sup +} extracted at 50 kV through a {phi} 6 mm aperture were produced by the PMECRs at PKU. Their rms emittances are less than 0.2 {pi} mm mrad. Tungsten samples were irradiated by H{sup +} or He{sup +} beam extracted from this ion source and H/He holes and bubbles have been observed on the samples. A method to produce a high intensity H/He mixed beam to study synergistic effect is developed for nuclear material irradiation. To design a He{sup +} beam injector for coupled radio frequency quadruple and SFRFQ cavity, He{sup +} beam transmission experiments were carried out on PKU low energy beam transport test bench and the transmission was less than 50%. It indicated that some electrode modifications must be done to decrease the divergence of He{sup +} beam.

  5. Co-existence of phenylketonuria either with maple syrup urine disease or Sandhoff disease in two patients from Iran: emphasizing the role of consanguinity.

    PubMed

    Abiri, Maryam; Talebi, Saeed; Uitto, Jouni; Youssefian, Leila; Vahidnezhad, Hassan; Shirzad, Tina; Salehpour, Shadab; Zeinali, Sirous

    2016-10-01

    Most inborn errors of metabolism (IEMs) are inherited in an autosomal recessive manner. IEMs are one of the major concerns in Iran due to its extensive consanguineous marriages. Herein, we report two patients with two co-existent IEMs: a girl affected by classic phenylketonuria (PKU) and maple syrup urine disease (MSUD) and a male patient affected with Sandhoff disease and PKU, where Sandhoff disease was suspected due to the presence of a cherry-red spot in the eyes at 6 months which is unrelated to PKU. Sequencing of candidate genes in the first patient revealed one novel and three recurrent compound heterozygous mutations of p.Ser231Pro and p.Ala300Ser in the PAH gene and p.Glu330Lys and p.Arg170Cys mutations in the BCKDHB gene. Genetic testing results in the second patient showed previously reported homozygous mutations of p.Arg261Gln in the PAH and p.Arg533Cys mutation in the HEXB gene. Genetic testing confirmed the clinical diagnosis of both diseases in both patients. To the best of our knowledge; this is the first report of the co-existence of two distinct genetic disorders in two individuals from Iran. Co-existent different IEMs in patients complicated the clinical diagnosis and management of the diseases.

  6. Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria.

    PubMed

    Harding, C O; Gillingham, M B; Hamman, K; Clark, H; Goebel-Daghighi, E; Bird, A; Koeberl, D D

    2006-03-01

    Novel recombinant adeno-associated virus vectors pseudotyped with serotype 8 capsid (rAAV2/8) have recently shown exciting promise as effective liver-directed gene transfer reagents. We have produced a novel liver-specific rAAV2/8 vector expressing the mouse phenylalanine hydroxylase (Pah) cDNA and have administered this vector to hyperphenylalaninemic PAH-deficient Pah(enu2) mice, a model of human phenylketonuria (PKU). Our hypothesis was that this vector would produce sufficient hepatocyte transduction frequency and PAH activity to correct blood phenylalanine levels in murine PKU. Portal vein injection of recombinant AAV2/8 vector into five adult Pah(enu2) mice yielded complete and stable (up to 17 weeks) correction of serum phenylalanine levels. Liver PAH activity was corrected to 11.5+/-2.4% of wild type liver activity and was associated with a significant increase in phenylalanine clearance following parenteral phenylalanine challenge. Although questions of long-term safety and stability of expression remain, recombinant AAV2/8-mediated, liver-directed gene therapy is a promising novel treatment approach for PKU and allied inborn errors of metabolism.

  7. Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria

    PubMed Central

    Harding, CO; Gillingham, MB; Hamman, K; Clark, H; Goebel-Daghighi, E; Bird, A; Koeberl, DD

    2009-01-01

    Novel recombinant adeno-associated virus vectors pseudo-typed with serotype 8 capsid (rAAV2/8) have recently shown exciting promise as effective liver-directed gene transfer reagents. We have produced a novel liver-specific rAAV2/8 vector expressing the mouse phenylalanine hydroxylase (Pah) cDNA and have administered this vector to hyperphenylalaninemic PAH-deficient Pahenu2 mice, a model of human phenylketonuria (PKU). Our hypothesis was that this vector would produce sufficient hepatocyte transduction frequency and PAH activity to correct blood phenylalanine levels in murine PKU. Portal vein injection of recombinant AAV2/8 vector into five adult Pahenu2 mice yielded complete and stable (up to 17 weeks) correction of serum phenylalanine levels. Liver PAH activity was corrected to 11.5±2.4% of wild type liver activity and was associated with a significant increase in phenylalanine clearance following parenteral phenylalanine challenge. Although questions of long-term safety and stability of expression remain, recombinant AAV2/8-mediated, liver-directed gene therapy is a promising novel treatment approach for PKU and allied inborn errors of metabolism. PMID:16319949

  8. Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study.

    PubMed

    Trefz, Friedrich K; Burton, Barbara K; Longo, Nicola; Casanova, Mercedes Martinez-Pardo; Gruskin, Daniel J; Dorenbaum, Alex; Kakkis, Emil D; Crombez, Eric A; Grange, Dorothy K; Harmatz, Paul; Lipson, Mark H; Milanowski, Andrzej; Randolph, Linda Marie; Vockley, Jerry; Whitley, Chester B; Wolff, Jon A; Bebchuk, Judith; Christ-Schmidt, Heidi; Hennermann, Julia B

    2009-05-01

    To evaluate the ability of sapropterin dihydrochloride (pharmaceutical preparation of tetrahydrobiopterin) to increase phenylalanine (Phe) tolerance while maintaining adequate blood Phe control in 4- to 12-year-old children with phenylketonuria (PKU). This international, double-blind, randomized, placebo-controlled study screened for sapropterin response among 90 enrolled subjects in Part 1. In Part 2, 46 responsive subjects with PKU were randomized (3:1) to sapropterin, 20 mg/kg/d, or placebo for 10 weeks while continuing on a Phe-restricted diet. After 3 weeks, a dietary Phe supplement was added every 2 weeks if Phe control was adequate. The mean (+/-SD) Phe supplement tolerated by the sapropterin group had increased significantly from the pretreatment amount (0 mg/kg/d) to 20.9 (+/-15.4) mg/kg/d (P < .001) at the last visit at which subjects had adequate blood Phe control (<360 micromol/L), up to week 10. Over the 10-week period, the placebo group tolerated only an additional 2.9 (+/-4.0) mg/kg/d Phe supplement; the mean difference from the sapropterin group (+/-SE) was 17.7 +/- 4.5 mg/kg/d (P < .001). No severe or serious related adverse events were observed. Sapropterin is effective in increasing Phe tolerance while maintaining blood Phe control and has an acceptable safety profile in this population of children with PKU.

  9. Review of neonatal screening programme for phenylketonuria.

    PubMed Central

    Smith, I; Cook, B; Beasley, M

    1991-01-01

    OBJECTIVE--To review the neonatal screening programme during 1984-8. DESIGN--Analysis of data from screening laboratories and paediatricians. SUBJECTS--All live births in United Kingdom. MAIN OUTCOME MEASURES--Structure of programme; number of infants tested and number with phenylketonuria; number of infants missed; ages at testing and treatment. RESULTS--The proportion of infants tested approached 100%. The incidence of phenylketonuria was 11.7/100,000 births (445 subjects): 273 had classic phenylketonuria and three had defects of cofactor metabolism. One child with phenylketonuria was known to have been missed compared with three in 1979-83 and six in 1974-8. Seven subjects had been missed over the 15 years due to negative test results. All seven had been tested with the bacterial inhibition assay, although only 53% of infants had been so tested; the difference between the expected and observed proportion was significant (Fisher's exact test, p = 0.017). Eleven infants with classic phenylketonuria were not tested by 14 days of age and 23 (8%) did not start treatment until after 20 days, an improvement compared with 36 (15%) in 1979-83. There were, however, wide regional variations (0% to 27% treated after 20 days). CONCLUSION--The screening programme achieves high coverage and effectiveness, although some children are still missed. A national practice for screening may help reduce regional variations. PMID:1912773

  10. DNA methylation in the pathophysiology of hyperphenylalaninemia in the PAH(enu2) mouse model of phenylketonuria.

    PubMed

    Dobrowolski, S F; Lyons-Weiler, J; Spridik, K; Vockley, J; Skvorak, K; Biery, A

    2016-09-01

    Phenylalanine hydroxylase deficient phenylketonuria (PKU) is the paradigm for a treatable inborn error of metabolism where maintaining plasma phenylalanine (Phe) in the therapeutic range relates to improved clinical outcomes. While Phe is the presumed intoxicating analyte causal in neurologic damage, the mechanism(s) of Phe toxicity has remained elusive. Altered DNA methylation is a recognized response associated with exposure to numerous small molecule toxic agents. Paralleling this effect, we hypothesized that chronic Phe over-exposure in the brain would lead to aberrant DNA methylation with secondary influence upon gene regulation that would ultimately contribute to PKU neuropathology. The PAH(enu2) mouse models human PKU with intrinsic hyperphenylalaninemia, abnormal response to Phe challenge, and neurologic deficit. To examine this hypothesis, we assessed DNA methylation patterns in brain tissues using methylated DNA immunoprecipitation and paired end sequencing in adult PAH(enu2) animals maintained under either continuous dietary Phe restriction or chronic hyperphenylalaninemia. Heterozygous PAH(enu2/WT) litter mates served as controls for normal Phe exposure. Extensive repatterning of DNA methylation was observed in brain tissue of hyperphenylalaninemic animals while Phe restricted animals displayed an attenuated pattern of aberrant DNA methylation. Affected gene coding regions displayed aberrant hypermethylation and hypomethylation. Gene body methylation of noncoding RNA genes was observed and among these microRNA genes were prominent. Of particular note, observed only in hyperphenylalaninemic animals, was hypomethylation of miRNA genes within the imprinted Dlk1-Dio3 locus on chromosome 12. Aberrant methylation of microRNA genes influenced their expression which has secondary effects upon the expression of targeted protein coding genes. Differential hypermethylation of gene promoters was exclusive to hyperphenylalaninemic PAH(enu2) animals. Genes with

  11. Phenylketonuria

    MedlinePlus

    ... is a rare inherited disorder that causes an amino acid called phenylalanine to build up in your body. ... of the enzyme that's needed to process an amino acid called phenylalanine. A dangerous buildup of phenylalanine can ...

  12. Phenylketonuria

    MedlinePlus

    ... foods. There are special formulas for newborns. For older children and adults, the diet includes many fruits and vegetables. It also includes some low-protein breads, pastas and cereals. Nutritional formulas provide the vitamins and minerals you can' ...

  13. Biochemical Evaluation of Phenylalanine Ammonia Lyase from Endemic Plant Cyathobasis fruticulosa (Bunge) Aellen. for the Dietary Treatment of Phenylketonuria

    PubMed Central

    Aydaş, Selcen Babaoğlu; Aslım, Belma

    2016-01-01

    Summary Enzyme substitution therapy with the phenylalanine ammonia lyase (PAL) is a new approach to the treatment of patients with phenylketonuria (PKU). This enzyme is responsible for the conversion of phenylalanine to trans-cinnamic acid. We assessed the PAL enzyme of the endemic plant Cyathobasis fruticulosa (Bunge) Aellen. for its possible role in the dietary treatment of PKU. The enzyme was found to have a high activity of (64.9±0.1) U/mg, with the optimum pH, temperature and buffer (Tris–HCl and l-phenylalanine) concentration levels of pH=8.8, 37 °C and 100 mM, respectively. Optimum enzyme activity was achieved at pH=4.0 and 7.5, corresponding to pH levels of gastric and intestinal juice, and NaCl concentration of 200 mM. The purification of the enzyme by 1.87-fold yielded an activity of 98.6 U/mg. PAL activities determined by HPLC analyses before and after purification were similar. Two protein bands, one at 70 and the other at 23 kDa, were determined by Western blot analysis of the enzyme. This enzyme is a potential candidate for serial production of dietary food and biotechnological products. PMID:27956861

  14. Biochemical Evaluation of Phenylalanine Ammonia Lyase from Endemic Plant Cyathobasis fruticulosa (Bunge) Aellen. for the Dietary Treatment of Phenylketonuria.

    PubMed

    Şirin, Seda; Aydaş, Selcen Babaoğlu; Aslım, Belma

    2016-09-01

    Enzyme substitution therapy with the phenylalanine ammonia lyase (PAL) is a new approach to the treatment of patients with phenylketonuria (PKU). This enzyme is responsible for the conversion of phenylalanine to trans-cinnamic acid. We assessed the PAL enzyme of the endemic plant Cyathobasis fruticulosa (Bunge) Aellen. for its possible role in the dietary treatment of PKU. The enzyme was found to have a high activity of (64.9±0.1) U/mg, with the optimum pH, temperature and buffer (Tris-HCl and l-phenylalanine) concentration levels of pH=8.8, 37 °C and 100 mM, respectively. Optimum enzyme activity was achieved at pH=4.0 and 7.5, corresponding to pH levels of gastric and intestinal juice, and NaCl concentration of 200 mM. The purification of the enzyme by 1.87-fold yielded an activity of 98.6 U/mg. PAL activities determined by HPLC analyses before and after purification were similar. Two protein bands, one at 70 and the other at 23 kDa, were determined by Western blot analysis of the enzyme. This enzyme is a potential candidate for serial production of dietary food and biotechnological products.

  15. Accurate molecular diagnosis of phenylketonuria and tetrahydrobiopterin-deficient hyperphenylalaninemias using high-throughput targeted sequencing

    PubMed Central

    Trujillano, Daniel; Perez, Belén; González, Justo; Tornador, Cristian; Navarrete, Rosa; Escaramis, Georgia; Ossowski, Stephan; Armengol, Lluís; Cornejo, Verónica; Desviat, Lourdes R; Ugarte, Magdalena; Estivill, Xavier

    2014-01-01

    Genetic diagnostics of phenylketonuria (PKU) and tetrahydrobiopterin (BH4) deficient hyperphenylalaninemia (BH4DH) rely on methods that scan for known mutations or on laborious molecular tools that use Sanger sequencing. We have implemented a novel and much more efficient strategy based on high-throughput multiplex-targeted resequencing of four genes (PAH, GCH1, PTS, and QDPR) that, when affected by loss-of-function mutations, cause PKU and BH4DH. We have validated this approach in a cohort of 95 samples with the previously known PAH, GCH1, PTS, and QDPR mutations and one control sample. Pooled barcoded DNA libraries were enriched using a custom NimbleGen SeqCap EZ Choice array and sequenced using a HiSeq2000 sequencer. The combination of several robust bioinformatics tools allowed us to detect all known pathogenic mutations (point mutations, short insertions/deletions, and large genomic rearrangements) in the 95 samples, without detecting spurious calls in these genes in the control sample. We then used the same capture assay in a discovery cohort of 11 uncharacterized HPA patients using a MiSeq sequencer. In addition, we report the precise characterization of the breakpoints of four genomic rearrangements in PAH, including a novel deletion of 899 bp in intron 3. Our study is a proof-of-principle that high-throughput-targeted resequencing is ready to substitute classical molecular methods to perform differential genetic diagnosis of hyperphenylalaninemias, allowing the establishment of specifically tailored treatments a few days after birth. PMID:23942198

  16. A prospective population pharmacokinetic analysis of sapropterin dihydrochloride in infants and young children with phenylketonuria.

    PubMed

    Qi, Yulan; Mould, Diane R; Zhou, Huiyu; Merilainen, Markus; Musson, Donald G

    2015-02-01

    Untreated phenylketonuria (PKU), a hereditary metabolic disorder caused by a genetic mutation in phenylalanine hydroxylase (PAH), is characterized by elevated blood phenylalanine (Phe) and severe neurologic disease. Sapropterin dihydrochloride, a synthetic preparation of naturally occurring PAH cofactor tetrahydrobiopterin (BH4), activates residual PAH in a subset of patients, resulting in decreased blood Phe and increased Phe tolerance. The objective of this study was to determine the appropriate dose of sapropterin in pediatric patients (0-6 years). The study design used D-optimization and was prospectively powered to achieve precise estimates of clearance and volume of distribution. Oral sapropterin (5 or 20 mg/kg) was administered once daily. Sapropterin plasma concentrations were measured by a validated method. Population pharmacokinetic analysis was performed with NONMEM(®) version 7.2 on pooled data from 156 pediatric and adult PKU patients in two phase III clinical studies. The best pharmacokinetic model was a one-compartment model with an absorption lag, first-order input, and linear elimination, with a factor describing endogenous BH4 levels. Body weight was the only covariate significantly affecting sapropterin pharmacokinetics. Based on recommended dosing, exposure across age groups was comparable. The absorption rate and terminal half-life suggest flip-flop pharmacokinetic behavior where absorption is rate limiting. The effect of weight on sapropterin pharmacokinetics was significant and exposure was comparable across age groups; thus, weight-based dosing is appropriate. The doses selected for pediatric patients provided similar exposure as in adults. Given the slow absorption and elimination half-life, once-daily dosing is justified.

  17. Performance of children with phenylketonuria in the Developmental Screening Test--Denver II.

    PubMed

    Silva, Greyce Kelly da; Lamônica, Dionísia Aparecida Cusin

    2010-01-01

    phenylketonuria is an autosomal recessive disorder resulting from the mutation of a gene located in chromosome 12q22-24.1. to describe the performance of children with classic phenylketonuria, who were diagnosed and treated early, in the Development Screening Test Denver - II. participants were 20 children with phenylketonuria, ranging in age from 3 and 6 years, and 10 children with typical language development, paired by gender, age and socioeconomic level to the research group. The plasmatic phenylalanine measure and the neurological, psychological and social information were gathered in the data base of the Neonatal Screening Programs for Metabolic disorder. Assessment consisted on the application of the Development Screening Test Denver II. A descriptive statistical analysis and the Mann Whitney test were used in order to characterize the tested skills. For the measurements of the plasmatic phenylalanine blood levels the values considered for analysis were: below 2 mg/dL, above 4 mg/dL, reference values between 2 and 4 mg/dL, of all exams performed during the participants'lives; maximum and minimum values and values obtained on the day of the screening application. comparison between the groups indicated statistically significant differences for the personal-social and language areas. children who were diagnosed and treated early for phenylketonuria present deficits in the personal-social and language areas. Also, even when receiving follow-up and undergoing treatment, these children presented difficulties in maintaining normal plasmatic phenylalanine levels.

  18. Complexities of Parental Understanding of Phenylketonuria

    ERIC Educational Resources Information Center

    Sibinga, Maarten S.; Friedman, C. Jack

    1971-01-01

    Parental understanding of PKU, investigated through a questionnaire, was evaluated as to completeness and with respect to distortion. Education of parents was found to be unrelated to their understanding or tendency to distort. Effectiveness of the pediatrician's communication with parents is discussed. (Author/KW)

  19. Complexities of Parental Understanding of Phenylketonuria

    ERIC Educational Resources Information Center

    Sibinga, Maarten S.; Friedman, C. Jack

    1971-01-01

    Parental understanding of PKU, investigated through a questionnaire, was evaluated as to completeness and with respect to distortion. Education of parents was found to be unrelated to their understanding or tendency to distort. Effectiveness of the pediatrician's communication with parents is discussed. (Author/KW)

  20. Heat-transfer-based detection of SNPs in the PAH gene of PKU patients

    PubMed Central

    Vanden Bon, Natalie; van Grinsven, Bart; Murib, Mohammed Sharif; Yeap, Weng Siang; Haenen, Ken; De Ceuninck, Ward; Wagner, Patrick; Ameloot, Marcel; Vermeeren, Veronique; Michiels, Luc

    2014-01-01

    Conventional neonatal diagnosis of phenylketonuria is based on the presence of abnormal levels of phenylalanine in the blood. However, for carrier detection and prenatal diagnosis, direct detection of disease-correlated mutations is needed. To speed up and simplify mutation screening in genes, new technologies are developed. In this study, a heat-transfer method is evaluated as a mutation-detection technology in entire exons of the phenylalanine hydroxylase (PAH) gene. This method is based on the change in heat-transfer resistance (Rth) upon thermal denaturation of dsDNA (double-stranded DNA) on nanocrystalline diamond. First, ssDNA (single-stranded DNA) fragments that span the size range of the PAH exons were successfully immobilized on nanocrystalline diamond. Next, it was studied whether an Rth change could be observed during the thermal denaturation of these DNA fragments after hybridization to their complementary counterpart. A clear Rth shift during the denaturation of exon 5, exon 9, and exon 12 dsDNA was observed, corresponding to lengths of up to 123 bp. Finally, Rth was shown to detect prevalent single-nucleotide polymorphisms, c.473G>A (R158Q), c.932T>C (p.L311P), and c.1222C>T (R408W), correlated with phenylketonuria, displaying an effect related to the different melting temperatures of homoduplexes and heteroduplexes. PMID:24741310

  1. Adults with untreated phenylketonuria: out of sight, out of mind

    PubMed Central

    Murphy, Glynis H.; Johnson, Sally M.; Amos, Allayne; Weetch, Eleanor; Hoskin, Rosemary; Fitzgerald, Brian; Lilburn, Maggie; Robertson, Lesley; Lee, Philip

    2008-01-01

    Some people with phenylketonuria who were born before screening began were never treated and are still alive. Here we report that far fewer people with untreated phenylketonuria were detected than are thought to exist (about 2000). The majority of those traced had high support needs, challenging behaviour and other symptoms of phenylketonuria. No significant differences were found between those who had or had not tried the phenylalanine-restricted diet. A randomised controlled trial is required to examine the effect of trying the low-phenylalanine diet for people with untreated phenylketonuria. PMID:19043156

  2. PKU-RBRC Workshop on Transverse Spin

    SciTech Connect

    Avakian,H.; Bunce, G.; Yuan, F.

    2008-06-30

    Understanding the structure of the nucleon is a fundamental question in subatomic physics, and it has been under intensive investigation for the last several years. Modern research focuses in particular on the spin structure of the nucleon. Experimental and theoretical investigations worldwide over the last few decades have established that, contrary to nave quark model expectations, quarks carry only about 30% of the totd spin of the proton. The origin of the remaining spin is the key question in current hadronic physics and also the major driving forces for the current and future experiments, such as RHIC and CEBAF in US, JPARC in Japan, COMPASS at CERN in Europe, FAIR at GSI in Germany. Among these studies, the transverse-spin physics develops actively and rapidly in the last few years. Recent studies reveal that transverse-spin physics is closely related to many fundamental properties of the QCD dynamics such as the factorization, the non-trivial universality of the parton distribution and fragmentation functions. It was very timely to bring together the theorists and experimentalists in this field at this workshop to review and discuss the latest developments and future perspective in hadronic spin physics. This workshop was very success iu many aspects. First of all, it attracted almost every expert working in this field. We had more than eighty participants in total, among them 27 came from the US institutes, 13 from Europe, 3 from Korea, and 2 from Japan. The rest participants came from local institutes in China. Second, we arranged plenty physics presentations, and the program covers all recent progresses made in the last few years. In total, we had 47 physics presentations, and two round table discussions. The discussion sessions were especially very useful and very much appreciated by all participants. In addition, we also scheduled plenty time for discussion in each presentation, and the living discussions impressed and benefited all participants.

  3. Newborn screening 50 years later: access issues faced by adults with PKU

    PubMed Central

    Berry, Susan A.; Brown, Christine; Grant, Mitzie; Greene, Carol L.; Jurecki, Elaina; Koch, Jean; Moseley, Kathryn; Suter, Ruth; van Calcar, Sandra C.; Wiles, Judy; Cederbaum, Stephen

    2013-01-01

    Fifty years after the implementation of universal newborn screening programs for phenylketonuria, the first disease identified through newborn screening and considered a success story of newborn screening, a cohort of adults with phenylketonuria treated from birth provides valuable information about effects of long-term treatment for inborn errors of metabolism in general, and phenylketonuria specifically. For phenylketonuria, newborn screening allows early implementation of the phenylalanine-restricted diet, eliminating the severe neurocognitive and neuromotor impairment associated with untreated phenylketonuria. However, executive function impairments and psychiatric problems are frequently reported even for those treated early and continuously with the phenylalanine-restricted diet alone. Moreover, a large percentage of adults with phenylketonuria are reported as lost to follow-up by metabolic clinics. While a group of experts identified by the National Institutes of Health convenes to update treatment guidelines for phenylketonuria, we explore individual patient, social, and economic factors preventing >70% of adult phenylketonuria patients in the United States from accessing treatment. As more conditions are identified through newborn screening, factors affecting access to treatment grow in importance, and we must continue to be vigilant in assessing and addressing factors that affect patient treatment outcomes and not just celebrate amelioration of the most severe manifestations of disease. Genet Med 2013:15(8):591–599 PMID:23470838

  4. Phenylketonuria and Complex Spatial Visualization: An Analysis of Information Processing.

    ERIC Educational Resources Information Center

    Brunner, Robert L.; And Others

    1987-01-01

    The study of the ability of 16 early treated phenylketonuric (PKU) patients (ages 6-23 years) to solve complex spatial problems suggested that choice of problem-solving strategy, attention span, and accuracy of mental representation may be affected in PKU patients, despite efforts to maintain well-controlled phenylalanine concentrations in the…

  5. Phenylketonuria and Complex Spatial Visualization: An Analysis of Information Processing.

    ERIC Educational Resources Information Center

    Brunner, Robert L.; And Others

    1987-01-01

    The study of the ability of 16 early treated phenylketonuric (PKU) patients (ages 6-23 years) to solve complex spatial problems suggested that choice of problem-solving strategy, attention span, and accuracy of mental representation may be affected in PKU patients, despite efforts to maintain well-controlled phenylalanine concentrations in the…

  6. Mutation analysis in Turkish phenylketonuria patients.

    PubMed Central

    Ozgüç, M; Ozalp, I; Coşkun, T; Yilmaz, E; Erdem, H; Ayter, S

    1993-01-01

    Forty-four classical PKU patients have been screened for various mutations. The newly identified IVS 10 splicing mutation was found in 32% of the mutant alleles and comprises 74.5% of the mutations that could be typed: 261arg-gln (6.8%), 158arg-gly (2.3%), 252arg-trp (1.1%), 280glu-lys (-), and 272gly-stop (-) were the other mutations that were screened. Images PMID:8445616

  7. Study on urinary metabolic profile of phenylketonuria by micellar electrokinetic capillary chromatography with dual electrochemical detection--potential clinical application in fast diagnosis of phenylketonuria.

    PubMed

    Zhang, Dongli; Li, Wenli; Zhang, Junbo; Tang, Wanrong; Qian, Chenxu; Feng, Minghao; Chu, Qingcui; Ye, Jiannong

    2011-05-23

    The urinary metabolic marker compounds, namely phenylpyruvic acid (PPA), 2-hydroxyphenylacetic acid (oOPAA), 4-hydroxyphenylacetic acid (pOPAA), phenyllactic acid (PLA) and phenylacetic acid (PAA) of phenylketonuric individuals were detected by a novel method of micellar electrokinetic capillary chromatography with capacitively coupled contactless conductivity detection and amperometric detection (MECC-C(4)D/AD). Electrophoretic runs were performed in a 35 mmol L(-1) SDS/60 mmol L(-1) H(3)BO(3)-Na(2)B(4)O(7) running buffer (pH 8.2) at a separation voltage of 16 kV, and five marker compounds and the major coexisting compound uric acid (UA) could be well separated within 23 min. Highly linear response was obtained for five marker compounds over three orders of magnitude with detection limits ranging from 6.6×10(-6) to 6.4×10(-8) g mL(-1) (S/N=3). The proposed method has been used to detect the marker compounds simultaneously in urine samples with the advantages of obtaining more information about target analytes and avoiding redundant measurements and high assay cost. Urinary patterns in phenylketonuric babies were distinct and easily distinguished from those of healthy newborns. The proposed MECC-C(4)D/AD method could find clinical application in early noninvasive diagnosis of phenylketonuria (PKU), as significant differences could be found in the urinary content of five marker compounds among the phenylketonuric babies without or with dietotherapy and the healthy babies.

  8. Identification and Quantitation of Phenylalanine in the Brain of Patients with Phenylketonuria by Means of Localized in Vivo1H Magnetic-Resonance Spectroscopy

    NASA Astrophysics Data System (ADS)

    Kreis, R.; Pietz, J.; Penzien, J.; Herschkowitz, N.; Boesch, C.

    Localized proton MR spectroscopy was used to identify phenylalanine (PHE) and to quantitate its cerebral concentration in patients with type I phenylketonuria (PKU). Data acquisition was optimized for the detection of low-concentration metabolites, using a short TE (20 ms) double Hahn-echo localization sequence for large volumes within the head coil and for smaller volumes using a surface coil, Previously described methods to quantitate localized MR spectra were extended to cover the case of low-concentration metabolites, unevenly distributed in three brain compartments and measured in difference spectra only. PHE content was determined in difference spectra of four PKU patients with respect to normals and in one patient before and after an oral load of L-PHE, PHE concentrations of 0.3 to 0.6 mmol/kg brain tissue were obtained, resulting in a concentration gradient for PHE between blood and brain tissue of 2.4 to 3.0, No significant changes were found for the abundant metabolites in gray or white matter. Previously reported MRI changes were confirmed to be due to increased cerebro-spinal-fluid-like spaces.

  9. Diurnal variation of phenylalanine and tyrosine concentrations in adult patients with phenylketonuria: subcutaneous microdialysis is no adequate tool for the determination of amino acid concentrations

    PubMed Central

    2013-01-01

    Background Metabolic control and dietary management of patients with phenylketonuria (PKU) are based on single blood samples obtained at variable intervals. Sampling conditions are often not well-specified and intermittent variation of phenylalanine concentrations between two measurements remains unknown. We determined phenylalanine and tyrosine concentrations in blood over 24 hours. Additionally, the impact of food intake and physical exercise on phenylalanine and tyrosine concentrations was examined. Subcutaneous microdialysis was evaluated as a tool for monitoring phenylalanine and tyrosine concentrations in PKU patients. Methods Phenylalanine and tyrosine concentrations of eight adult patients with PKU were determined at 60 minute intervals in serum, dried blood and subcutaneous microdialysate and additionally every 30 minutes postprandially in subcutaneous microdialysate. During the study period of 24 hours individually tailored meals with defined phenylalanine and tyrosine contents were served at fixed times and 20 min bicycle-ergometry was performed. Results Serum phenylalanine concentrations showed only minor variations while tyrosine concentrations varied significantly more over the 24-hour period. Food intake within the patients’ individual diet had no consistent effect on the mean phenylalanine concentration but the tyrosine concentration increased up to 300% individually. Mean phenylalanine concentration remained stable after short-term bicycle-exercise whereas mean tyrosine concentration declined significantly. Phenylalanine and tyrosine concentrations in dried blood were significantly lower than serum concentrations. No close correlation has been found between serum and microdialysis fluid for phenylalanine and tyrosine concentrations. Conclusions Slight diurnal variation of phenylalanine concentrations in serum implicates that a single blood sample does reliably reflect the metabolic control in this group of adult patients. Phenylalanine

  10. A limited spectrum of phenylalanine hydroxylase mutations is observed in phenylketonuria patients in western Poland and implications for treatment with 6R tetrahydrobiopterin.

    PubMed

    Dobrowolski, Steven F; Borski, K; Ellingson, C C; Koch, R; Levy, H L; Naylor, E W

    2009-06-01

    Phenylketonuria (PKU) is an autosomal recessive defect in hepatic metabolism of phenylalanine, which is secondary to mutations in the phenylalanine hydroxylase (PAH) gene. Sixty-seven ethnically Polish PKU patients, followed at the Outpatient Department of Pediatrics and Developmental Medicine in Poznan, Poland, were assessed for mutations in the PAH gene. Two mutations were identified in 61 of 67 patients and a single mutation was identified in the remaining six patients. The four most prevalent mutations (p.R408W, 68%; c.1066-11G>A, 6%; c.1315+1G>A, 5.2%; c.822-832delGCCCATGTATA, 3.7%) accounted for 83% of the mutant alleles. Fifteen additional mutations were identified of which most (13/15) were observed in an individual patient. Before knowledge of PAH genotypes, 19 patients were challenged with a 20 mg kg(-1) dose of 6R tetrahydrobiopterin (BH(4)) and serum phenylalanine concentration was monitored in hospital over 24 h. Two patients responded to the BH(4) challenge with a reduction of serum phenylalanine concentration >30% from baseline. PAH genotypes of the two responsive patients would have been predicted, as they contained mutations recognized as BH(4) responsive, whereas the 17 patients who were unresponsive would have been predicted as their mutations were either recognized as non-responsive or were highly deleterious frame-shift mutations. Overall, only 7.5% (5/ 67) of patients had PAH mutations recognized as responsive to co-factor therapy. Among the PKU patients from western Poland, PAH mutations responsive to BH(4) therapy are poorly represented; therefore, genotyping may be useful for identifying candidate patients likely to respond to BH(4) before physiological challenge.

  11. Estimating the probability of IQ impairment from blood phenylalanine for phenylketonuria patients: a hierarchical meta-analysis.

    PubMed

    Fonnesbeck, Christopher J; McPheeters, Melissa L; Krishnaswami, Shanthi; Lindegren, Mary Louise; Reimschisel, Tyler

    2013-09-01

    Though the control of blood phenylalanine (Phe) levels is essential for minimizing impairment in individuals with phenylketonuria (PKU), the empirical basis for the selection of specific blood Phe levels as targets has not been evaluated. We evaluated the current evidence that particular Phe levels are optimal for minimizing or avoiding cognitive impairment in individuals with PKU. This work uses meta-estimates of blood Phe-IQ correlation to predict the probability of low IQ for a range of Phe levels. We believe this metric is easily interpretable by clinicians, and hence useful in making recommendations for Phe intake. The median baseline association of Phe with IQ was estimated to be negative, both in the context of historical (median = -0.026, 95 % BCI = [-0.040, -0.013]) and concurrent (-0.007, [-0.014, 0.000]) measurement of Phe relative to IQ. The estimated additive fixed effect of critical period Phe measurement was also nominally negative for historical measurement (-0.010, [-0.022, 0.003]) and positive for concurrent measurement (0.007, [-0.018, 0.035]). Probabilities corresponding to historical measures of blood Phe demonstrated an increasing chance of low IQ with increasing Phe, with a stronger association seen between blood Phe measured during the critical period than later. In contrast, concurrently-measured Phe was more weakly correlated with the probability of low IQ, though the correlation is still positive, irrespective of whether Phe was measured during the critical or non-critical period. This meta-analysis illustrates the utility of a Bayesian hierarchical approach for not only combining information from a set of candidate studies, but also for combining different types of data to estimate parameters of interest.

  12. [Anxiety driven atypical eating disorder in the course of phenylketonuria].

    PubMed

    Rapps, Nora; Mack, Isabelle; Herrmann-Werner, Anne; Zipfel, Stephan; Teufel, Martin

    2015-07-01

    Phenylketonuria is the most common genetic disease in amino acid metabolism. We report the case of a 22-year old patient with phenylketonuria and psychological symptoms. After early treatment, phenylalanine levels had been controlled and were within target area. Clinical interview and psychometrics showed atypical eating disorder and anxiety disorder. Possible toxic effects and psychological factors may play a role in pathogenesis. Most likely the frequency of eating disorders and anxiety disorders in phenylketonuria is underestimated. © Georg Thieme Verlag KG Stuttgart · New York.

  13. Phenylketonuria: treatment in adolescence and adult life.

    PubMed

    Brenton, D P; Tarn, A C; Cabrera-Abreu, J C; Lilburn, M

    1996-07-01

    In our clinic the decision on whether to continue with dietary treatment of phenylketonuria or not is left to each adolescent and adult patient after the advantages and disadvantages, as discussed in this paper, of continuing diet have been presented to them. As a result 61 of 132 patients have stopped diet or declined to restart and only 4 of them have phenylalanine values below 1000 mumol/l. Seventy-one patients have remained on diet or started again with phenylalanine values below 1000 mumol/l in 58 of them. This series of 132 excludes women who returned to diet to conceive.

  14. Application of natural and amplification created restriction sites for the diagnosis of PKU mutations.

    PubMed Central

    Eiken, H G; Odland, E; Boman, H; Skjelkvåle, L; Engebretsen, L F; Apold, J

    1991-01-01

    PCR amplification, either conventional, or as site directed mutagenesis using primers with mismatched 3'-ends, followed by restriction endonuclease digestion, provides rapid, non-isotope assays of known mutations in the human phenylalanine hydroxylase gene. Such assays were shown to have the potential to detect all of the 18 presently reported phenylketonuria mutations. The practical applicability of this approach was demonstrated for eight mutations in Norwegian phenylketonuria patients, among them the most common ones. Images PMID:1851292

  15. Progressive neuropsychiatric manifestations of phenylketonuria in adulthood.

    PubMed

    Daelman, L; Sedel, F; Tourbah, A

    2014-04-01

    Neuropsychiatric signs and MRI abnormalities can occur in patients with phenylketonuria in adulthood. We describe clinical and radiological features of phenylketonuric patients and we discuss the advantage of continuing diet in adulthood. We report late onset neuropsychiatric symptoms of four phenylketonuric patients (33-45years) diagnosed in infancy and report the case of a patient (33years) diagnosed with phenylketonuria because of late onset neurological signs. We describe clinical and radiological features of these 5 patients, and their evolution under diet and propose a review of the literature. The main neurological abnormalities in phenylketonuric patients diagnosed in infancy are: brisk reflexes, spastic paraparesis, psychiatric signs that appear 10.5years after the diet arrest. A leukoencephalopathy was present in 93% of cases and 91.7% improve clinically after poor phenylalanine diet reintroduction. In 4 patients, neurological abnormalities (spastic paraparesis, dementia, Parkinsonism) led to the late diagnosis. Two of them had a leukoencephalopathy on brain MRI. Patients had high levels of phenylalanine (above 1500μmol/L) when neuropsychiatric signs occurred. Improvement after diet suggests that hyperphenylalaninemia has a direct toxic effect on the brain. The long-term follow-up of phenylketonuric patients is mandatory to depict and treat neurological complications in time. Diet reintroduction is efficacious in most cases. Copyright © 2014. Published by Elsevier Masson SAS.

  16. Development of micellar electro kinetic chromatography for the separation and quantitation of L-valine, L-leucine, L-isoleucin and L-phenylalanine in human plasma and comparison with HPLC.

    PubMed

    Darvish, M; Ebrahimi, S A; Ghadam, P

    2007-08-01

    Phenylketonuria (PKU) and Maple Syrup Urine Disease (MSUD) are two inborn metabolic diseases which are carried by autosomal recessive genes in man. These genetic errors result in accumulation of phenylalanine (in PKU) or valine, leucine and isoluecin (in MSUD). At high concentrations, amongst other problems, these amino acids cause mental retardation. However if detected early after birth, using special diets and other forms of therapy, mental abnormalities can be prevented. As a result in many countries screening of infants for MSUD and PKU, by measuring plasma amino acids has become a routine neonatal test. Capillary Electrophoresis (CE) assays have a number of advantages over the traditional chromatography techniques (such as GC or HPLC). These include low cost, high speed of analysis and high resolution. These characteristics, make CE an ideal method for the screening of inborn errors of metabolism. We developed a CE assay based on pre-column derivatisation of amino acids with phenylisothiocyanate. This conjugate has strong absorbance at 254 nm. CE was carried out using a Spectraphoresis 1000 instrument, fitted with 40 cm of a 25 microm capillary, at 17 degrees C. A running voltage of 18KV was used to separate the amino acid mixture in an electrophoretic buffer containing 45 mM imidazole, 6 mM borate and 208 mM SDS, fixed at pH 9 with 2-N-morpholino ethane sulfonic acid. The assay was calibrated using various concentrations of amino acid standards. LOD, LOQ, recovery, inter-day and intra-day variations of the assay were determined. Also, levels of the 4 amino acids in normal and abnormal plasma were determined and compared with HPLC.

  17. Classroom Demonstration of a Spot Test for Phenylpyruvic Acid and Its Relationship to Phenylketonuria

    NASA Astrophysics Data System (ADS)

    Halkides, Christopher J.

    2004-03-01

    A classroom demonstration of a spot test for phenylketonuria using ferric chloride is discussed. The chemistry is similar to that used in Phenistix test strips. Some background information on screening infants for phenylketonuria is also given.

  18. Duty factor variation possibility from 1% to 100% with PKU microwave driven Cs-free volume H- sources

    NASA Astrophysics Data System (ADS)

    Peng, S. X.; Zhang, T.; Ren, H. T.; Zhang, A. L.; Xu, Y.; Zhang, J. F.; Guo, Z. Y.; Chen, J. E.

    2016-02-01

    Microwave driven cesium-free volume H- sources, that have the ability to deliver tens of mA H- at 35 keV both in CW and 10% duty factor (100 Hz/1 ms), were developed at Peking University (PKU) [S. X. Peng et al., in Proceeding of IPAC 2015, WEPWA027, Richmond, Virginia, USA, 3-8 May 2015]. Recently, special efforts were paid on the investigation of duty factor variation possibility from 1% to 100% with them. Most of the experiments were carried out with a pulsed length (τ) of 1 ms and different intervals of 99 ms, 49 ms, 39 ms, 29 ms, 19 ms, 9 ms, 4 ms, 2 ms, 1 ms, 0.5 ms, and 0 ms, respectively. Other experiments were focused on CW operation and fixed duty factor of 1%. Experimental results prove that PKU H- sources can deliver tens of mA H- at duty factor from 1% to 100%. The RF power efficiency increases steadily with the increasing of duty factor from 1% to CW at a fixed pulsed length. Under a given duty factor and pulsed length, RF power efficiency keeps constant and the H- current increases with RF power linearly. Details will be presented in the paper.

  19. Clinical relevance of the discrepancy in phenylalanine concentrations analyzed using tandem mass spectrometry compared with ion-exchange chromatography in phenylketonuria.

    PubMed

    Stroup, Bridget M; Held, Patrice K; Williams, Phillip; Clayton, Murray K; Murali, Sangita G; Rice, Gregory M; Ney, Denise M

    2016-03-01

    Metabolic control of phenylketonuria (PKU) and compliance with the low-phenylalanine (phe) diet are frequently assessed by measuring blood phe concentrations in dried blood spots (DBS) collected by patients instead of plasma phe concentrations. Our objective was to investigate the difference in blood phe concentrations in DBS collected by subjects and analyzed using either a validated newborn screening tandem mass spectrometry (MS/MS) protocol or ion-exchange chromatography (IEC) compared to plasma phe concentrations obtained simultaneously and analyzed using IEC. Three to four fasting blood samples were obtained from 29 subjects with PKU, ages 15-49 years. Capillary blood was spotted on filter paper by each subject and the DBS analyzed using both MS/MS and IEC. Plasma was isolated from venous blood and analyzed using IEC. Blood phe concentrations in DBS analyzed using MS/MS are 28% ± 1% (n = 110, p < 0.0001) lower than plasma phe concentrations analyzed using IEC resulting in a blood phe concentration of 514 ± 23 μmol/L and a plasma phe concentration of 731 ± 32 μmol/L (mean ± SEM). This discrepancy is larger when plasma phe is > 600 μmol/L. Due to the large variability across subjects of 13.2%, a calibration factor to adjust blood phe concentrations is not recommended. Analysis of DBS using IEC reduced the discrepancy to 15 ± 2% lower phe concentrations compared to plasma analyzed using IEC (n = 38, p = 0.0001). This suggests that a major contributor to the discrepancy in phe concentrations is the analytical method. Use of DBS analyzed using MS/MS to monitor blood phe concentrations in individuals with PKU yields significantly lower phe levels compared to plasma phe levels analyzed using IEC. Optimization of current testing methodologies for measuring phe in DBS, along with patient education regarding the appropriate technique for spotting blood on filter paper is needed to improve the accuracy of using DBS to measure phe

  20. Clinical relevance of the discrepancy in phenylalanine concentrations analyzed using tandem mass spectrometry compared with ion-exchange chromatography in phenylketonuria

    PubMed Central

    Stroup, Bridget M.; Held, Patrice K.; Williams, Phillip; Clayton, Murray K.; Murali, Sangita G.; Rice, Gregory M.; Ney, Denise M.

    2016-01-01

    Introduction Metabolic control of phenylketonuria (PKU) and compliance with the low-phenylalanine (phe) diet are frequently assessed by measuring blood phe concentrations in dried blood spots (DBS) collected by patients instead of plasma phe concentrations. Objective Our objective was to investigate the difference in blood phe concentrations in DBS collected by subjects and analyzed using either a validated newborn screening tandem mass spectrometry (MS/MS) protocol or ion-exchange chromatography (IEC) compared to plasma phe concentrations obtained simultaneously and analyzed using IEC. Design Three to four fasting blood samples were obtained from 29 subjects with PKU, ages 15–49 years. Capillary blood was spotted on filter paper by each subject and the DBS analyzed using both MS/MS and IEC. Plasma was isolated from venous blood and analyzed using IEC. Results Blood phe concentrations in DBS analyzed using MS/MS are 28% ± 1% (n = 110, p < 0.0001) lower than plasma phe concentrations analyzed using IEC resulting in a blood phe concentration of 514 ± 23 μmol/L and a plasma phe concentration of 731 ± 32 μmol/L (mean ± SEM). This discrepancy is larger when plasma phe is > 600 μmol/L. Due to the large variability across subjects of 13.2%, a calibration factor to adjust blood phe concentrations is not recommended. Analysis of DBS using IEC reduced the discrepancy to 15 ± 2% lower phe concentrations compared to plasma analyzed using IEC (n = 38, p = 0.0001). This suggests that a major contributor to the discrepancy in phe concentrations is the analytical method. Conclusion Use of DBS analyzed using MS/MS to monitor blood phe concentrations in individuals with PKU yields significantly lower phe levels compared to plasma phe levels analyzed using IEC. Optimization of current testing methodologies for measuring phe in DBS, along with patient education regarding the appropriate technique for spotting blood on filter paper is needed to improve

  1. Molecular analysis of contiguous exons of the phenylalanine hydroxylase gene: identification of a new PKU mutation.

    PubMed Central

    Dianzani, I; Camaschella, C; Saglio, G; Ferrero, G B; Ramus, S; Ponzone, A; Cotton, R G

    1993-01-01

    A modified application of the chemical cleavage of mismatch (CCM) method has been used to screen three contiguous exons (exons 9, 10, and 11) of the phenylalanine hydroxylase gene in 17 Italian PKU patients. A new nonsense heterozygous C-->G transversion within exon 11 (S359X) was identified in a single patient. Only one of the four mutations previously reported in this DNA region in Caucasians was found. This lesion, IVS X-546, was detected in five of the 34 PKU alleles examined. Our results underline the versatility of the CCM method for scanning a gene for multiple mutations. Images PMID:8097261

  2. Molecular analysis of contiguous exons of the phenylalanine hydroxylase gene: identification of a new PKU mutation.

    PubMed

    Dianzani, I; Camaschella, C; Saglio, G; Ferrero, G B; Ramus, S; Ponzone, A; Cotton, R G

    1993-03-01

    A modified application of the chemical cleavage of mismatch (CCM) method has been used to screen three contiguous exons (exons 9, 10, and 11) of the phenylalanine hydroxylase gene in 17 Italian PKU patients. A new nonsense heterozygous C-->G transversion within exon 11 (S359X) was identified in a single patient. Only one of the four mutations previously reported in this DNA region in Caucasians was found. This lesion, IVS X-546, was detected in five of the 34 PKU alleles examined. Our results underline the versatility of the CCM method for scanning a gene for multiple mutations.

  3. Risk factors for developing mineral bone disease in phenylketonuric patients.

    PubMed

    Mirás, Alicia; Bóveda, M Dolores; Leis, María R; Mera, Antonio; Aldámiz-Echevarría, Luís; Fernández-Lorenzo, José R; Fraga, José M; Couce, María L

    2013-03-01

    There is a compromised bone mass in phenylketonuria patients compared with normal population, but the mechanisms responsible are still a matter of investigation. In addition, tetrahydrobiopterin therapy is a new option for a significant proportion of these patients and the prevalence of mineral bone disease (MBD) in these patients is unknown. We conducted a cross-sectional observational study including 43 phenylketonuric patients. Bone densitometry, nutritional assessment, physical activity questionnaire, biochemical parameters, and molecular study were performed in all patients. Patients were stratified by phenotype, age and type of treatment. The MBD prevalence in phenylketonuria was 14%. Osteopenic and osteoporotic (n=6 patients) had an average daily natural protein intake significantly lower than the remaining (n=37) patients with PKU (14.33 ± 8.95 g vs 21.25 ± 20.85 g). Besides, a lower body mass index was found. There were no statistical differences in physical activity level, calcium, phosphorus and fat intake, and in phenylalanine, vitamin D, paratohormone, docosahexaenoic and eicosapentaenoic acid blood levels. Mutational spectrum was found in up to 30 different PAH genotypes and no relationship was established among genotype and development of MBD. None of the twelve phenylketonuric patients treated with tetrahydrobiopterin (27.9%), for an average of 7.1 years, developed MBD. Natural protein intake and blood levels of eicosapentaenoic acid were significantly higher while calcium intake was lower in these patients. This study shows that the decrease in natural protein intake can play an important role in MBD development in phenylketonuric patients. Therapy with tetrahydrobiopterin allows a more relaxed protein diet, which is associated with better bone mass.

  4. Tryptophan Metabolism in a Patient with Phenylketonuria and Scleroderma

    PubMed Central

    Drummond, Keith N.; Michael, Alfred F.; Good, Robert A.

    1966-01-01

    Phenylketonuria and severe focal scleroderma were observed in a white male child. This is the first instance in which the association of these two rare disorders has been reported. Studies carried out on this patient provide a possible explanation for the abnormalities of indole metabolism in phenylketonuria. On an unrestricted diet, when serum phenylalanine levels were elevated, excessive urinary excretion of indolic tryptophan metabolites was seen 18-24 hours after oral tryptophan loading, and tryptophan was demonstrable in the stool. This was not observed when the serum phenylalanine was within normal limits on a low phenylalanine diet. Impaired intestinal tryptophan absorption secondary to elevated serum phenylalanine, by providing tryptophan substrate for bacterial degradation to indolic compounds which are absorbed and excreted in the urine, may partially explain the abnormalities of indole metabolism in phenylketonuria. ImagesFig. 1 PMID:5929533

  5. A randomized, placebo-controlled, double-blind trial of supplemental docosahexaenoic acid on cognitive processing speed and executive function in females of reproductive age with phenylketonuria: A pilot study☆, ☆☆

    PubMed Central

    Yi, S.H.L.; Kable, J.A.; Evatt, M.L.; Singh, R.H.

    2014-01-01

    Low blood docosahexaenoic acid (DHA) is reported in patients with phenylketonuria (PKU); however, the functional implications in adolescents and adults are unknown. This pilot study investigated the effect of supplemental DHA on cognitive performance in 33 females with PKU ages 12–47 years. Participants were randomly assigned to receive DHA (10 mg/kg/day) or placebo for 4.5 months. Performance on cognitive processing speed and executive functioning tasks was evaluated at baseline and follow up. Intention-to-treat and per protocol analyses were performed. At follow up, biomarkers of DHA status were significantly higher in the DHA-supplemented group. Performance on the cognitive tasks and reported treatment-related adverse events did not differ. While no evidence of cognitive effect was seen, a larger sample size is needed to be conclusive, which may not be feasible in this population. Supplementation was a safe and effective way to increase biomarkers of DHA status (www.clinicaltrials.gov; Identifier: NCT00892554). PMID:22000478

  6. Final intelligence in late treated patients with phenylketonuria.

    PubMed

    Trefz, F K; Cipcic-Schmidt, S; Koch, R

    2000-10-01

    Despite neonatal screening programmes, there is still a number of patients with phenylketonuria who are not diagnosed and start treatment late. The question in this study was to evaluate which factors will contribute, other than the quality and duration of dietary treatment, to final outcome in late treated patients with phenylketonuria. We retrospectively analysed the data of 40 patients with phenylketonuria, of whom 2 patients at 35 and 24 years of age had a normal IQ despite never being treated. In 38 patients starting dietary treatment between 0.7 and 7 years of age, mean IQ/DQ at diagnosis was 52.7 (SD = 16) (mean age 2.5 years), final IQ (mean age 33.5 years) was 79.0 (SD = 16), the difference was highly significant (P < 0.0001). Important factors for the final intelligence in adult late treated patients with phenylketonuria were onset (r = -0.46, P < 0.009) and DQ/IQ (r = 0.51, P < 0.002) when dietary treatment was started. Thus, in late treated patients with phenylketonuria, in addition to the quality and duration of treatment, the outcome is mainly influenced by the age of starting treatment and also by the intellectual status of the patient. In one of the two patients with normal intelligence, nuclear magnetic resonance spectroscopy showed that brain phenylalanine was undetectable even though blood phenylalanine was 30 mg/dl. A second metabolic disorder may protect these patients from severe brain damage. These data indicate that brain damage in untreated or late treated patients with phenylketonuria is influenced by various genetic factors.

  7. Results of loading doses of aspartame by two phenylketonuric (PKU) children compared with two normal children.

    PubMed

    Koch, R; Schaeffler, G; Shaw, N F

    1976-11-01

    Separate tolerance tests with aspartame at 34 mg/kg-day and phenylalanine at 19 mg/kg-day were compared. The results reveal that slight serum elevation of phenylalanine and tyrosine occurred in the two PKU and the normal healthy adolescents. It would appear that the phenylalanine in the sweetener aspartame is small enough to be of little clinical significance.

  8. Phenylketonuria presenting in adulthood as progressive spastic paraparesis with dementia

    PubMed Central

    Kasim, S; Moo, L; Zschocke, J; Jinnah, H

    2001-01-01

    A 57 year old woman living independently in the community presented with four years of progressive spastic paraparesis and dementia. An extensive evaluation for the usual causes of these difficulties was unrevealing, but her serum phenylalanine concentration was markedly elevated and genetic analysis demonstrated mutations in the phenylalanine hydroxylase gene consistent with classic phenylketonuria. A protein restricted diet was associated with improvement in her condition. Although untreated phenylketonuria is typically associated with severe neurological dysfunction beginning in early childhood, this case shows that disability may be delayed until adulthood.

 PMID:11723206

  9. Prefrontal Cortex Cognitive Deficits in Children Treated Early and Continuously for PKU.

    ERIC Educational Resources Information Center

    Diamond, Adele; Prevor, Meredith B.; Druin, Donald P.; Callender, Glenda

    1997-01-01

    Hypothesized that elevated ratio of phenylalanine to tyrosine in blood of children with phenylketonuria uniquely affects cognitive functions dependent on prefrontal cortex because of the special sensitivity of prefrontally projecting dopamine neurons to small decreases in tyrosine. Found that children whose phenylalanine levels were three to five…

  10. Prefrontal Cortex Cognitive Deficits in Children Treated Early and Continuously for PKU.

    ERIC Educational Resources Information Center

    Diamond, Adele; Prevor, Meredith B.; Druin, Donald P.; Callender, Glenda

    1997-01-01

    Hypothesized that elevated ratio of phenylalanine to tyrosine in blood of children with phenylketonuria uniquely affects cognitive functions dependent on prefrontal cortex because of the special sensitivity of prefrontally projecting dopamine neurons to small decreases in tyrosine. Found that children whose phenylalanine levels were three to five…

  11. OMEGA-3 LONG-CHAIN POLYUNSATURATED FATTY ACIDS IN OLDER CHILDREN

    USDA-ARS?s Scientific Manuscript database

    Phenylketonuria (PKU), the most prevalent inborn error of metabolism, is usually secondary to low hepatic activity of phenylalanine hydroxylase, the enzyme that catalyzes conversion of phenylalanine to tyrosine. Growth and development of infants and children with PKU who are managed by mandatory n...

  12. Newborn Screening for Genetic-Metabolic Diseases: Progress, Principles and Recommendations.

    ERIC Educational Resources Information Center

    Holtzman, Neil A.

    This monograph, designed for persons involved in the organization and regulation of screening of newborns infants for Phenylketonuria (PKU) and other genetic-metabolic diseases reviews new developments in the field, makes recommendations, and provides information about specific conditions other than PKU that are detectable by screening. Discussed…

  13. Phase 1 Trial of Subcutaneous rAvPAL-PEG in Subjects with Phenylketonuria

    PubMed Central

    Longo, Nicola; Harding, Cary O.; Burton, Barbara K.; Grange, Dorothy K.; Vockley, Jerry; Wasserstein, Melissa; Rice, Gregory M.; Musson, Donald G.; Gu, Zhonghua; Sile, Saba

    2014-01-01

    Objective Phenylketonuria is an inherited disease caused by impaired activity of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine, leading to accumulation of phenylalanine and subsequent neurocognitive dysfunction. A phenylalanine-restricted diet initiated early in life can ameliorate the toxic effects of phenylalanine. However, the diet is onerous and compliance is extremely difficult. Phenylalanine ammonia lyase (PAL) is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. This Phase 1, multicenter clinical trial evaluated the safety, tolerability, pharmacokinetics and efficacy of rAvPAL-PEG (recombinant Anabaena variabilis PAL produced in E. coli conjugated with polyethylene glycol [PEG] to reduce immunogenicity) in reducing phenylalanine levels in subjects with phenylketonuria. Methods Single subcutaneous injections of rAvPAL-PEG in escalating doses (0·001, 0·003, 0·01, 0·03, and 0·1 mg/kg) were administered to 25 adults with phenylketonuria recruited from those attending metabolic clinics in North America whose blood phenylalanine concentrations were ≥600 μmol/L. Results The most frequently reported adverse events were injection-site reactions and dizziness. Reactions were self-limited without sequelae. During the trial, two subjects had adverse reactions to intramuscular (IM) medroxyprogesterone acetate, a drug containing polyethylene glycol as an excipient. Three subjects developed a generalized skin rash at the highest rAvPAL-PEG dose (0·1 mg/kg). Drug levels peaked ∼5 days after the injection. Treatment was effective in reducing blood phenylalanine in all five subjects receiving the highest dose (0·1 mg/kg, mean percent change of -58 from baseline), with a nadir ∼6 days after injection and inverse correlation between drug and phenylalanine concentrations in plasma. Phenylalanine concentrations returned to near-baseline levels ∼20 days after the single injection. Conclusions

  14. PHENYLKETONURIA, AN INHERITED METABOLIC DISORDER ASSOCIATED WITH MENTAL RETARDATION.

    ERIC Educational Resources Information Center

    CENTERWALL, WILLARD R.; CENTERWALL, SIEGRIED A.

    ADDRESSED TO PUBLIC HEALTH WORKERS AND PHYSICIANS IN GENERAL PRACTICE, THE PAMPHLET INTRODUCES METHODS OF DETECTING AND MANAGING PHENYLKETONURIA, AN INHERITED METABOLIC DISORDER ASSOCIATED WITH MENTAL RETARDATION. INFORMATION, UPDATED FROM THE 1961 EDITION, IS INCLUDED ON THE INCIDENCE AND GENETICS, BIOCHEMISTRY, AND CLINICAL COURSE OF THE…

  15. Collaborative Study of Children Treated for Phenylketonuria: Study Design

    ERIC Educational Resources Information Center

    Williamson, Malcolm; And Others

    1977-01-01

    Available from: Arthur Retlaw and Associates, Inc., Suite 2080, 1603 Orrington Avenue, Evanston, Illinois 60201. Described is a study in which a large sample of children (n=444) with phenylketonuria (an inborn metabolic error usually related to impaired cognitive ability) were treated under controlled conditions from near birth to 6 years of age.…

  16. Speech and Language Skills in Children with Early Treated Phenylketonuria.

    ERIC Educational Resources Information Center

    Ozanne, Anne E.; And Others

    1990-01-01

    The study of 29 children, age 7 months to 16 years, with early treated phenylketonuria found no significant differences on speech and/or language measures when compared with controls matched for age, sex, and socioeconomic level. Examination of individual scores, however, did reveal linguistic impairment in a small number of subjects. (Author/JDD)

  17. [Phenotypic and molecular characterization of a Colombian family with phenylketonuria].

    PubMed

    Gélvez, Nancy; Acosta, Johana; López, Greizy; Castro, Derly; Prieto, Juan Carlos; Bermúdez, Martha; Tamayo, Marta L

    2016-09-01

    Phenylketonuria is a metabolic disorder characterized by severe neurological involvement and behavioral disorder, whose early diagnosis enables an effective treatment to avoid disease sequelae, thus changing the prognosis. Objective: To characterize a family with phenylketonuria in Colombia at clinical, biochemical and molecular levels. Materials and methods: The population consisted of seven individuals of a consanguineous family with four children with suggestive symptoms of phenylketonuria. After signing an informed consent, blood and urine samples were taken for colorimetric tests and high performance liquid and thin layer chromatographies. DNA extraction and sequencing of the 13 exons of the PAH gene were performed in all subjects. We designed primers for each exon with the Primer 3 software using automatic sequencing equipment Abiprism 3100 Avant. Sequences were analyzed using the SeqScape, v2.0, software. Results: We described the clinical and molecular characteristics of a Colombian family with phenylketonuria and confirmed the presence of the mutation c.398_401delATCA. We established a genotype-phenotype correlation, highlighting the interesting clinical variability found among the affected patients despite having the same mutation in all of them. Conclusions: Early recognition of this disease is very important to prevent its neurological and psychological sequelae, given that patients reach old age without diagnosis or proper management.

  18. Collaborative Study of Children Treated for Phenylketonuria: Study Design

    ERIC Educational Resources Information Center

    Williamson, Malcolm; And Others

    1977-01-01

    Available from: Arthur Retlaw and Associates, Inc., Suite 2080, 1603 Orrington Avenue, Evanston, Illinois 60201. Described is a study in which a large sample of children (n=444) with phenylketonuria (an inborn metabolic error usually related to impaired cognitive ability) were treated under controlled conditions from near birth to 6 years of age.…

  19. Speech and Language Skills in Children with Early Treated Phenylketonuria.

    ERIC Educational Resources Information Center

    Ozanne, Anne E.; And Others

    1990-01-01

    The study of 29 children, age 7 months to 16 years, with early treated phenylketonuria found no significant differences on speech and/or language measures when compared with controls matched for age, sex, and socioeconomic level. Examination of individual scores, however, did reveal linguistic impairment in a small number of subjects. (Author/JDD)

  20. Recommendations for protein and amino acid intake in phenylketonuria patients.

    PubMed

    Przyrembel, H

    1996-07-01

    Nitrogen requirement in phenylketonuria patients is similar to that of normal persons. Prescribed protein intake for patients should be based on age-related safe levels of protein intake modified by the digestibility-corrected amino acid score. Adequate energy intakes and distribution of dietary protein over meals are important determinants for the quality of dietary treatment.

  1. PHENYLKETONURIA, AN INHERITED METABOLIC DISORDER ASSOCIATED WITH MENTAL RETARDATION.

    ERIC Educational Resources Information Center

    CENTERWALL, WILLARD R.; CENTERWALL, SIEGRIED A.

    ADDRESSED TO PUBLIC HEALTH WORKERS AND PHYSICIANS IN GENERAL PRACTICE, THE PAMPHLET INTRODUCES METHODS OF DETECTING AND MANAGING PHENYLKETONURIA, AN INHERITED METABOLIC DISORDER ASSOCIATED WITH MENTAL RETARDATION. INFORMATION, UPDATED FROM THE 1961 EDITION, IS INCLUDED ON THE INCIDENCE AND GENETICS, BIOCHEMISTRY, AND CLINICAL COURSE OF THE…

  2. Preservation of high phenylalanine ammonia lyase activities in roots of Japanese Striped corn: a potential oral therapeutic to treat phenylketonuria.

    PubMed

    López-Villalobos, Arturo; Lücker, Joost; López-Quiróz, Ana Angela; Yeung, Edward C; Palma, Kristoffer; Kermode, Allison R

    2014-06-01

    Phenylketonuria (PKU) is an inherited metabolic disorder caused by deficient phenylalanine hydroxylase (PAH) activity, the enzyme responsible for the disposal of excess amounts of the essential amino acid phenylalanine (Phe). Phenylalanine ammonia-lyase (PAL, EC 4.3.1.5) has potential to serve as an enzyme substitution therapy for this human genetic disease. Using 7-day-old Japanese Striped corn seedlings (Japonica Striped maize, Zea mays L. cv. japonica) that contain high activities of PAL, we investigated a number of methods to preserve the roots as an intact food and for long-term storage. The cryoprotectant effects of maple syrup and other edible sugars (mono- and oligosaccharides) were evaluated. Following thawing, the preserved roots were then examined to determine whether the rigid plant cell walls could protect the PAL enzyme from proteolysis during simulated (in vitro) digestion comprised of gastric and intestinal phases. While several treatments led to retention of PAL activity during freezing, upon thawing and in vitro digestion, root tissues that had been previously frozen in the presence of maple syrup exhibited the highest residual PAL activities (∼50% of the initial enzyme activity), in marked contrast to all of the treatments using other edible sugars. The structural integrity of the root cells, and the stability of the functional PAL tetramer were also preserved with the maple syrup protocol. These results have significance for the formulation of oral enzyme/protein therapeutics. When plant tissues are adequately preserved, the rigid cell walls constitute a protective barrier even under harsh (e.g. gastrointestinal-like) conditions.

  3. Doxycycline hinders phenylalanine fibril assemblies revealing a potential novel therapeutic approach in phenylketonuria

    PubMed Central

    De Luigi, Ada; Mariani, Alessandro; De Paola, Massimiliano; Re Depaolini, Andrea; Colombo, Laura; Russo, Luca; Rondelli, Valeria; Brocca, Paola; Adler-Abramovich, Lihi; Gazit, Ehud; Del Favero, Elena; Cantù, Laura; Salmona, Mario

    2015-01-01

    A new paradigm for the aetiopathology of phenylketonuria suggests the presence of amyloid-like assemblies in the brains of transgenic mouse models and patients with phenylketonuria, possibly shedding light on the selective cognitive deficit associated with this disease. Paralleling the amyloidogenic route that identifies different stages of peptide aggregation, corresponding to different levels of toxicity, we experimentally address for the first time, the physico-chemical properties of phenylalanine aggregates via Small Angle, Wide Angle X-ray Scattering and Atomic Force Microscopy. Results are consistent with the presence of well-structured, aligned fibres generated by milliMolar concentrations of phenylalanine. Moreover, the amyloid-modulating doxycycline agent affects the local structure of phenylalanine aggregates, preventing the formation of well-ordered crystalline structures. Phenylalanine assemblies prove toxic in vitro to immortalized cell lines and primary neuronal cells. Furthermore, these assemblies also cause dendritic sprouting alterations and synaptic protein impairment in neurons. Doxycycline counteracts these toxic effects, suggesting an approach for the development of future innovative non-dietary preventive therapies. PMID:26510963

  4. Doxycycline hinders phenylalanine fibril assemblies revealing a potential novel therapeutic approach in phenylketonuria.

    PubMed

    De Luigi, Ada; Mariani, Alessandro; De Paola, Massimiliano; Re Depaolini, Andrea; Colombo, Laura; Russo, Luca; Rondelli, Valeria; Brocca, Paola; Adler-Abramovich, Lihi; Gazit, Ehud; Del Favero, Elena; Cantù, Laura; Salmona, Mario

    2015-10-29

    A new paradigm for the aetiopathology of phenylketonuria suggests the presence of amyloid-like assemblies in the brains of transgenic mouse models and patients with phenylketonuria, possibly shedding light on the selective cognitive deficit associated with this disease. Paralleling the amyloidogenic route that identifies different stages of peptide aggregation, corresponding to different levels of toxicity, we experimentally address for the first time, the physico-chemical properties of phenylalanine aggregates via Small Angle, Wide Angle X-ray Scattering and Atomic Force Microscopy. Results are consistent with the presence of well-structured, aligned fibres generated by milliMolar concentrations of phenylalanine. Moreover, the amyloid-modulating doxycycline agent affects the local structure of phenylalanine aggregates, preventing the formation of well-ordered crystalline structures. Phenylalanine assemblies prove toxic in vitro to immortalized cell lines and primary neuronal cells. Furthermore, these assemblies also cause dendritic sprouting alterations and synaptic protein impairment in neurons. Doxycycline counteracts these toxic effects, suggesting an approach for the development of future innovative non-dietary preventive therapies.

  5. Improvements of PKU PMECRIS for continuous hundred hours CW proton beam operation

    SciTech Connect

    Peng, S. X. Ren, H. T.; Zhang, T.; Zhang, J. F.; Xu, Y.; Guo, Z. Y.; Zhang, A. L.; Chen, J. E.

    2016-02-15

    In order to improve the source stability, a long term continuous wave (CW) proton beam experiment has been carried out with Peking University compact permanent magnet 2.45 GHz ECR ion source (PKU PMECRIS). Before such an experiment a lot of improvements and modifications were completed on the source body, the Faraday cup and the PKU ion source test bench. At the beginning of 2015, a continuous operation of PKU PMECRIS for 306 h with more than 50 mA CW beam was carried out after success of many short term tests. No plasma generator failure or high voltage breakdown was observed during that running period and the proton source reliability is near 100%. Total beam availability, which is defined as 35-keV beam-on time divided by elapsed time, was higher than 99% [S. X. Peng et al., Chin. Phys. B 24(7), 075203 (2015)]. A re-inspection was performed after another additional 100 h operation (counting time) and no obvious sign of component failure was observed. Counting the previous source testing time together, this PMECRs longevity is now demonstrated to be greater than 460 h. This paper is mainly concentrated on the improvements for this long term experiment.

  6. Neuropsychological Studies on Adolescents with Phenylketonuria Returned to Phenylalanine-Restricted Diets.

    ERIC Educational Resources Information Center

    Clarke, J. T. R.; And Others

    1987-01-01

    The study evaluated neuropsychological effects of high or low phenylalanine diets on nine phenylketonuric (PKU) adolescents who had been on unrestricted diets for 2 to 11 years. Results found that PKU adolescents on unrestricted diets have a neuropsychological deficit which can be partly reversed by returning to dietary phenylalanine restricted…

  7. Duty factor variation possibility from 1% to 100% with PKU microwave driven Cs-free volume H{sup −} sources

    SciTech Connect

    Peng, S. X. Zhang, T.; Ren, H. T.; Xu, Y.; Zhang, J. F.; Guo, Z. Y.; Zhang, A. L.; Chen, J. E.

    2016-02-15

    Microwave driven cesium-free volume H{sup −} sources, that have the ability to deliver tens of mA H{sup −} at 35 keV both in CW and 10% duty factor (100 Hz/1 ms), were developed at Peking University (PKU) [S. X. Peng et al., in Proceeding of IPAC 2015, WEPWA027, Richmond, Virginia, USA, 3–8 May 2015]. Recently, special efforts were paid on the investigation of duty factor variation possibility from 1% to 100% with them. Most of the experiments were carried out with a pulsed length (τ) of 1 ms and different intervals of 99 ms, 49 ms, 39 ms, 29 ms, 19 ms, 9 ms, 4 ms, 2 ms, 1 ms, 0.5 ms, and 0 ms, respectively. Other experiments were focused on CW operation and fixed duty factor of 1%. Experimental results prove that PKU H{sup −} sources can deliver tens of mA H{sup −} at duty factor from 1% to 100%. The RF power efficiency increases steadily with the increasing of duty factor from 1% to CW at a fixed pulsed length. Under a given duty factor and pulsed length, RF power efficiency keeps constant and the H{sup −} current increases with RF power linearly. Details will be presented in the paper.

  8. Intellectual and Developmental Status in Children With Hyperphenylalaninemia and PKU Who Were Screened in a National Program

    PubMed Central

    Aghasi, Parisa; Setoodeh, Arya; Sayarifard, Azadeh; Rashidiyan, Maryam; Sayarifard, Fatemeh; Rabbani, Ali; Mahmoudi-Gharaei, Javad

    2015-01-01

    Background: Hyperphenylalaninemia (HPA) and Phenylkeonuria (PKU) are metabolic errors caused by deficiency of phenylalanine hydroxylase enzyme, which results in increased level of phenylalanine. This increase is toxic to the growing brain. Objectives: The purpose of this study was to compare the intellectual and developmental status in HPA and PKU children with normal population in national screening program. Patients and Methods: In a historical cohort study, 41 PKU patients who had the inclusion criteria and 41 healthy children were evaluated. Wechsler preschool and primary scale of intelligence-3rd edition (WPPI-3) was used in order to assess the intellectual status of children 4 years and older and Ages and stages questionnaire (ASQ) was used to assess the developmental status of children 5 years and younger. Results: In intellectual test comparison, the two groups showed significant difference in Wechsler’s performance intelligence score and some performance subscales (P-value < 0.01). In comparison of developmental status, no significant difference was observed between the two groups (P-value > 0.05). Conclusions: Even with early diagnosis and treatment of PKU patients, these children show some deficiencies intellectually compared to normal children. This study emphasizes on necessity for screening intellectual and developmental status of PKU patients so that effective medical or educational measures can taken in case of deficiencies. PMID:26635939

  9. Protein substitute for children and adults with phenylketonuria.

    PubMed

    Yi, Sarah H L; Singh, Rani H

    2015-02-27

    Phenylketonuria is an inherited metabolic disorder characterised by an absence or deficiency of the enzyme phenylalanine hydroxylase. The aim of treatment is to lower blood phenylalanine concentrations to the recommended therapeutic range to prevent developmental delay and support normal growth. Current treatment consists of a low-phenylalanine diet in combination with a protein substitute which is free from or low in phenylalanine. Guidance regarding the use, dosage, and distribution of dosage of the protein substitute over a 24-hour period is unclear, and there is variation in recommendations among treatment centres. This is an update of a Cochrane review first published in 2005, and previously updated in 2008. To assess the benefits and adverse effects of protein substitute, its dosage, and distribution of dose in children and adults with phenylketonuria who are adhering to a low-phenylalanine diet. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which consists of references identified from comprehensive electronic database searches and hand searches of relevant journals and abstract books of conference proceedings. We also contacted manufacturers of the phenylalanine-free and low-phenylalanine protein substitutes for any data from published and unpublished randomised controlled trials.Date of the most recent search of the Group's Inborn Errors of Metabolism Trials Register: 03 April 2014. All randomised or quasi-randomised controlled trials comparing: any dose of protein substitute with no protein substitute; an alternative dosage; or the same dose, but given as frequent small doses throughout the day compared with the same total daily dose given as larger boluses less frequently. Both authors independently extracted data and assessed trial quality. Three trials (69 participants) are included in this review. One trial investigated the use of protein substitute in 16 participants, while a further two trials investigated the

  10. Lorentz detuning and tuning system study of 3+1/2cell DC-SC photo-injector for PKU-FEL

    NASA Astrophysics Data System (ADS)

    Xu, Wen-Can; Quan, Sheng-Wen; Zhao, Kui; Zhu, Feng

    2008-03-01

    A 3+1/2cell DC-SC photo-injector for PKU-FEL facility is under development, which is an upgrade design of the successful 1+1/2cell DC-SC photo-injector. The Lorentz detuning and tuning structure for the 3+1/2cell superconducting cavity is presented in this paper. The Lorentz force detuning coefficient is 1.2 Hz/(MV/m)2 with double stiffening rings for the half cell and single stiffening rings between the adjacent TESLA cells. With the special stiffening structure, the 3+1/2cell whole cavity needs only one tuner. The influences of the tuning on frequency shift, field flatness and average gradient are discussed in this paper. The simulation results show that the stiffening rings' design is successful. Supported by Major State Basic Research Development Program of China (2002CB713600)

  11. Application of Stacking Technique in ANA: Method and Practice with PKU Seismological Array

    NASA Astrophysics Data System (ADS)

    Liu, J.; Tang, Y.; Ning, J.; Chen, Y. J.

    2010-12-01

    Cross correlation of ambient noise records is now routinely used to get dispersion curve and then do seismic tomography; however little attention has been paid to array techniques. We will present a spacial-stacking method to get high resolution dispersion curves and show practices with the observation data of PKU seismological array. Experiential Green Functions are generally obtained by correlation between two stations, and then the dispersion curves are obtained from the analysis of FTAN. Popular method to get high resolution dispersion curves is using long time records. At the same time, if we want to get effectual signal, the distance between the two stations must be at least 3 times of the longest wavelength. So we need both long time records and appropriate spaced stations. Now we use a new method, special-stacking, which allows shorter observation period and utilizes observations of a group of closely distributed stations to get fine dispersion curves. We correlate observations of every station in the station group with those of a far station, and then stack them together. However we cannot just simply stack them unless the stations in the station group at a circle, of which the center is the far station owing to dispersion characteristics of the Rayleigh waves. Thus we do antidispersion on the observation data of every station in the array, then do stacking. We test the method using the theoretical seismic surface wave records which obtained by qseis06 compiled by Rongjiang Wang both with and without noise. For the cases of three imaginary stations (distance is 1 degree) have the same underground structure and without noise, result is that the center station had the same dispersion with and without spacial-stacking. Then we add noise to the theoretical records. The center station's dispersion curves obtained by our method are much closer to the dispersion curve without noise than contaminated ones. We can see that our method has improved the resolution of

  12. Challenges and pitfalls in the management of phenylketonuria.

    PubMed

    Feillet, François; van Spronsen, Francjan J; MacDonald, Anita; Trefz, Friedrich K; Demirkol, Mübeccel; Giovannini, Marcello; Bélanger-Quintana, Amaya; Blau, Nenad

    2010-08-01

    Despite recent advances in the management of phenylketonuria and hyperphenylalaninemia, important questions on the management of this disorder remain unanswered. Consensus exists on the need for neonatal screening and early treatment, yet disagreement persists over threshold levels of blood phenylalanine for starting treatment, target blood phenylalanine levels, and the management of older patient groups. The mainstay of treatment is a phenylalanine-restricted diet, but its application varies between and within countries. Beyond diet treatment, there is a lack of consensus on the use of newer treatments such as tetrahydrobiopterin. Although neonatal screening and early treatment has meant that most well-treated children grow up with near-normal IQ scores, the effect of relaxing metabolic control on cognitive and executive function later in life is still not fully understood. Although it is clear from the available literature that the active control of blood phenylalanine levels is of vital importance, there are other treatment-related factors that affect outcome. A uniform and firmly evidence-based approach to the management of phenylketonuria is required.

  13. Dental disease indices and caries related oral microflora in children with phenylketonuria.

    PubMed

    Lucas, V S; Contreras, A; Loukissa, M; Roberts, G J

    2001-01-01

    The purpose of this study was to investigate the dental caries, plaque and gingivitis indices and caries related oral flora in children with classic phenylketonuria. Forty-one children at The Great Ormond Street Hospital for Children and controls were included in the study. The main findings were: No significant difference in the decayed, missing and filled surfaces of the primary and permanent teeth between the phenylketonuria children and the controls. A significantly greater mean plaque score for the control children compared with the phenylketonuria children (p < 0.01) for the permanent teeth only. A significantly greater number of white opacities in the permanent teeth of the phenylketonuria group compared with the control group (p < 0.02). No significant differences in the caries related microflora.

  14. Brain dysfunction in phenylketonuria: is phenylalanine toxicity the only possible cause?

    PubMed

    van Spronsen, F J; Hoeksma, Marieke; Reijngoud, Dirk-Jan

    2009-02-01

    In phenylketonuria, mental retardation is prevented by a diet that severely restricts natural protein and is supplemented with a phenylalanine-free amino acid mixture. The result is an almost normal outcome, although some neuropsychological disturbances remain. The pathology underlying cognitive dysfunction in phenylketonuria is unknown, although it is clear that the high plasma concentrations of phenylalanine influence the blood-brain barrier transport of large neutral amino acids. The high plasma phenylalanine concentrations increase phenylalanine entry into brain and restrict the entry of other large neutral amino acids. In the literature, emphasis has been on high brain phenylalanine as the pathological substrate that causes mental retardation. Phenylalanine was found to interfere with different cerebral enzyme systems. However, apart from the neurotoxicity of phenylalanine, a deficiency of the other large neutral amino acids in brain may also be an important factor affecting cognitive function in phenylketonuria. Cerebral protein synthesis was found to be disturbed in a mouse model of phenylketonuria and could be caused by shortage of large neutral amino acids instead of high levels of phenylalanine. Therefore, in this review we emphasize the possibility of a different idea about the pathogenesis of mental dysfunction in phenylketonuria patients and the aim of treatment strategies. The aim of treatment in phenylketonuria might be to normalize cerebral concentrations of all large neutral amino acids rather than prevent high cerebral phenylalanine concentrations alone. In-depth studies are necessary to investigate the role of large neutral amino acid deficiencies in brain.

  15. Dietary glycemic index, glycemic load and metabolic profile in children with phenylketonuria.

    PubMed

    Moretti, F; Pellegrini, N; Salvatici, E; Rovelli, V; Banderali, G; Radaelli, G; Scazzina, F; Giovannini, M; Verduci, E

    2017-02-01

    No data exist in the current literature on the glycemic index (GI) and glycemic load (GL) of the diet of phenylketonuric (PKU) children. The aims of this study were to examine the dietary GI and GL in PKU children on a low-phenylalanine (Phe)-diet and to evaluate whether an association may exist between the carbohydrate quality and the metabolic profile. Twenty-one PKU children (age 5-11 years) and 21 healthy children, gender and age matched, were enrolled. Dietary (including GI and GL) and blood biochemical assessments were performed. No difference was observed for daily energy intake between PKU and healthy children. Compared to healthy controls, PKU children consumed less protein (p = 0.001) and fat (p = 0.028), and more carbohydrate (% of total energy, p = 0.004) and fiber (p = 0.009). PKU children had higher daily GI than healthy children (mean difference (95% confidence interval), 13.7 (9.3-18.3)) and higher GL (31.7 (10.1-53.2)). PKU children exhibited lower blood total and low density lipoprotein cholesterol (LDL) levels (p < 0.01) and higher triglyceride level (p = 0.014) than healthy children, while glucose and insulin concentrations did not differ. In PKU children the dietary GL was associated with triglyceride glucose index (Spearman's correlation coefficient = 0.515, p = 0.034). In PKU children a relationship of the dietary treatment with GI and GL, blood triglycerides and triglyceride glucose index may exist. Improvement towards an optimal diet for PKU children could include additional attention to the management of dietary carbohydrate quality. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

  16. A late-diagnosed phenylketonuria case presenting with autism spectrum disorder in early childhood.

    PubMed

    Mazlum, Betül; Anlar, Banu; Kalkanoğlu-Sivri, H Serap; Karlı-Oğuz, Kader; Özusta, Şeniz; Ünal, Fatih

    2016-01-01

    Phenylketonuria is one of the most prevalent autosomal recessive hereditary disorders in Turkey. If untreated, it results in severe brain damage and can also be associated with autism in certain patients. We present a three-year old boy who exhibited the symptoms of autism and was subsequently diagnosed with phenylketonuria. This case illustrates that because the majority of autism cases are idiopathic, an occasional patient with a metabolic disorder might be overlooked especially in the era of newborn screening. We also discuss the possible pathogenetic processes leading to autistic symptoms in phenylketonuria, and wish to draw attention to the possibility of cases missed in the screening program because of less than 100% coverage or insufficient food intake before blood sampling. Clinicians should keep in mind the possibility of treatable disorders in children with autism even when such disorders appear unlikely.

  17. Early dietary treated patients with phenylketonuria can achieve normal growth and body composition.

    PubMed

    Rocha, Júlio C; van Spronsen, Francjan J; Almeida, Manuela F; Ramos, Elisabete; Guimarães, João T; Borges, Nuno

    2013-01-01

    In the past, overtreatment may have resulted in growth impairment in patients with phenylketonuria. The paper aims to investigate height and body composition in early treated patients with phenylketonuria who were diagnosed between 1981 and 2008. A cross-sectional study of 89 patients with phenylketonuria and 78 controls aged (mean ± SD, in years) 14.4 ± 6.6 and 15.9 ± 7.1, respectively, was undertaken, including anthropometric and body composition evaluation using bioelectrical impedance. Median Phe concentrations in the last year before study enrollment were used as a measure of metabolic control. Natural protein and amino acid mixture intakes were recorded in patients. No statistically significant differences were found on height z-scores between patients and controls aged less than 19 years (p=0.301), although all patients with classical phenylketonuria revealed negative height z-scores, resulting in a mean ± SD of -0.65 ± 0.41. Among participants aged 19 years or more, median (p25-p75) of height was significantly higher in controls [168.0 cm (159.2-174.8)] than in patients [160.5 cm (151.9-167.5)] (p=0.017). No significant differences were found between patients and controls regarding fat mass, fat free mass, muscular mass, body cell mass index and phase angle. Our results suggest that early and continuously treated patients with phenylketonuria born after 1992 can achieve normal growth and body composition, although the negative height z-score in patients with classical phenylketonuria strengthens the continuous need to optimize the quality of their protein intake. © 2013 Elsevier Inc. All rights reserved.

  18. Neuropsychological assessment among children and adolescents with phenylketonuria and hyperphenylalaninemia and its relationship with plasma phenylalanine levels.

    PubMed

    González García, María B; Conde-Guzon, Pablo; Alcalde Martín, Carlos; Conde-Guzon, María J; Velasco Zúñiga, Roberto

    2017-06-01

    Although with early treatment phenylketonuria patients may have average intelligence levels, it is important to optimize the nutritional management to maintain adequate phenylalanine levels, so that patients can develop their intellectal potential free of abnormalities in their daily activities due to deficits of cognitive executive functions. This study presents a series of 26 patients, diagnosed and treated early, who underwent a psychometric evaluation together with phenylalanine determinations along their lives, and at the time of doing the tests. A trend is observed towards a reverse relationship between IQ and concurrent phenylalanine concentration, phenylalanine median and phenylalanine/tyrosine ratio. Likewise, a trend towards a negative relationship is observed between executive functions and concurrent phenylalanine values along patients' lives. Sociedad Argentina de Pediatría.

  19. 6R-tetrahydrobiopterin treated PKU patients below 4 years of age: Physical outcomes, nutrition and genotype.

    PubMed

    Aldámiz-Echevarría, Luis; Bueno, María A; Couce, María L; Lage, Sergio; Dalmau, Jaime; Vitoria, Isidro; Llarena, Marta; Andrade, Fernando; Blasco, Javier; Alcalde, Carlos; Gil, David; García, María C; González-Lamuño, Domingo; Ruiz, Mónica; Ruiz, María A; Peña-Quintana, Luis; González, David; Sánchez-Valverde, Felix

    2015-05-01

    Phenylalanine-restricted diets have proven effective in treating phenylketonuria. However, such diets have occasionally been reported to hinder normal development. Our study aimed to assess whether treating 0-4-year-old phenylketonuric patients with 6R-tetrahydrobiopterin might prevent growth retardation later in life. We conducted a longitudinal retrospective study which examined anthropometric characteristics of phenylketonuric patients on 6R-tetrahydrobiopterin therapy (22 subjects), and compared them with a group of phenylketonuric patients on protein-restricted diets (44 subjects). Nutritional issues were also considered. We further explored possible relationships between mutations in the PAH gene, BH4 responsiveness and growth outcome. No significant growth improvements were observed in either the group on 6R-tetrahydrobiopterin treatment (height Z-score: initial= -0.57 ± 1.54; final=-0.52 ± 1.29; BMI Z-score: initial=0.17 ± 1.05; final=0.18 ± 1.00) or the diet-only group (height Z-score: initial=-0.92 ± 0.96; final= -0.78 ± 1.08; BMI Z-score: initial=0.17 ± 0.97; final=-0.07 ± 1.03) over the 1-year observation period. Furthermore, we found no significant differences (p>0.05) between the two groups at any of the time points considered (0, 6 and 12 months). Patients on 6R-tetrahydrobiopterin increased their phenylalanine intake (from 49.1 [25.6-60.3] to 56.5 [39.8-68.3] mgkg(-1)day(-1)) and natural protein intake (from 1.0 [0.8-1.7] to 1.5 [1.0-1.8] g kg(-1)day(-1)), and some patients managed to adopt normal diets. Higher phenylalanine and natural protein intakes were positively correlated with better physical outcomes in the diet-only group (p<0.05). No correlation was found between patient genotype and physical outcomes, results being similar regardless of the nutritional approach used. We did not detect any side effects due to 6R-tetrahydrobiopterin administration. Our study indicates that treating 0-4-year-old phenylketonuric patients with 6R

  20. In vitro residual activity of phenylalanine hydroxylase variants and correlation with metabolic phenotypes in PKU.

    PubMed

    Trunzo, Roberta; Santacroce, Rosa; Shen, Nan; Jung-Klawitter, Sabine; Leccese, Angelica; De Girolamo, Giuseppe; Margaglione, Maurizio; Blau, Nenad

    2016-12-05

    Hyperphenylalaninemias (HPAs) are genetic diseases predominantly caused by a wide range of variants in the phenylalanine hydroxylase (PAH) gene. In vitro expression analysis of PAH variants offers the opportunity to elucidate the molecular mechanisms involved in HPAs and to clarify whether a disease-associated variant is genuinely pathogenic, while investigating the severity of a metabolic phenotype, and determining how a variant exerts its deleterious effects on the PAH enzyme. To study the effects of gene variants on PAH activity, we investigated eight variants: c.611A>G (p.Y204C), c.635T>C (p.L212P), c.746T>C (p.L249P), c.745C>T (p.L249F), c.809G>A (p.R270K), c.782G>C (p.R261P), c.587C>A (p.S196Y) and c.1139C>T (p.T380M), associated with different phenotypic groups. Transient expression of mutant full-length cDNAs in COS-7 cells yielded PAH proteins with PAH activity levels between 7% and 51% compared to the wild-type enzyme. With one exception (p.Y204C, which had no significant impact on PAH function), lower PAH activity was associated with a more severe phenotype (e.g. p.L249P with 7% PAH activity, 100% of classic PKU and no BH4 responsiveness), while higher activity correlated with milder phenotypes (e.g. p.T380M with 28% PAH activity, 97% of mild HPA and 83% of BH4 responsiveness). The results of the in vitro residual PAH activity have major implications, both for our understanding of genotype-phenotype correlations, and thereby existing inconsistencies, but also for the elucidation of the molecular basis of tetrahydrobiopterin (BH4) responsiveness.

  1. Late-diagnosed phenylketonuria in an eight-year-old boy with dyslexia and attention-deficit hyperactivity disorder.

    PubMed

    Yıldız, Yılmaz; Dursun, Ali; Tokatlı, Ayşegül; Coşkun, Turgay; Sivri, Hatice Serap

    2016-01-01

    Phenylketonuria, previously a common cause of severe intellectual disability, is a metabolic disorder now promptly diagnosed and effectively treated thanks to newborn screening programs. Here, we report a male patient presenting with dyslexia and attention-deficit hyperactivity disorder, who was diagnosed with mild phenylketonuria at eight years of age. Earlier recognition and treatment before the establishment of irreversible brain damage would have resulted in better neurobehavioural outcomes. Classical phenylketonuria and milder phenotypes of phenylalanine hydroxylase deficiency need to be considered in the differential diagnosis of all cognitive and behavioural problems of unknown cause.

  2. Diet in children with phenylketonuria and risk of cardiovascular disease: A narrative overview.

    PubMed

    Verduci, E; Banderali, G; Moretti, F; Lassandro, C; Cefalo, G; Radaelli, G; Salvatici, E; Giovannini, M

    2016-03-01

    The aim of this paper is to review the possible relationship of restricted phenylalanine (Phe) diet, a diet primarily comprising low-protein foods and Phe-free protein substitutes, with major cardiovascular risk factors (overweight/obesity, blood lipid profile, plasma levels of homocysteine, adiponectin and free asymmetric dimethylarginine (ADMA), oxidative stress and blood pressure) in PKU children. In PKU children compliant with diet, blood total cholesterol, low-density lipoprotein cholesterol (LDL-C), plasma ADMA levels and diastolic pressure were reported to be lower and plasma adiponectin levels to be higher compared to healthy controls. No difference was observed in overweight prevalence and in high-density lipoprotein cholesterol (HDL-C) levels. Inconsistent results were found for plasma homocysteine levels and antioxidant status. PKU children compliant with diet seem to display non-different cardiovascular risks compared with the healthy population. Well-designed longitudinal studies are required to clarify the potential underlying mechanisms associated with PKU and cardiovascular risk factors. Copyright © 2015 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

  3. Parental Problem-Solving Skills, Stress, and Dietary Compliance in Phenylketonuria.

    ERIC Educational Resources Information Center

    Fehrenbach, Annette M. B.; Peterson, Lizette

    1989-01-01

    Parents of 30 children with phenylketonuria, classified as being in good or poor dietary control, engaged in verbal and written problem-solving situations under conditions of both high and low time-pressure induced stress. Overall, compliant parents gave higher quality verbal and written problem-solving solutions than noncompliant parents.…

  4. Intelligence Patterns among Children with High-Functioning Autism, Phenylketonuria, and Childhood Head Injury.

    ERIC Educational Resources Information Center

    Dennis, Maureen; Lockyer, Linda; Lazenby, Anne L.; Donnelly, Ruth E.; Wilkinson, Margaret; Schoonheyt, Wanda

    1999-01-01

    A study compared the Comprehension: Block Design IQ subtest pattern of 8 children with autism and 24 children with developmental and acquired frontal lobe disorders. Found that children with autism showed low social comprehension related to visual spatial ability, a profile which was shared by children with poorly controlled Phenylketonuria. (CR)

  5. [The mutation analysis of PAH gene and prenatal diagnosis in classical phenylketonuria family].

    PubMed

    Yan, Yousheng; Hao, Shengju; Yao, Fengxia; Sun, Qingmei; Zheng, Lei; Zhang, Qinghua; Zhang, Chuan; Yang, Tao; Huang, Shangzhi

    2014-12-01

    To characterize the mutation spectrum of phenylalanine hydroxylase (PAH) gene and perform prenatal diagnosis for families with classical phenylketonuria. By stratified sequencing, mutations were detected in the exons and flaking introns of PAH gene of 44 families with classical phenylketonuria. 47 fetuses were diagnosed by combined sequencing with linkage analysis of three common short tandem repeats (STR) (PAH-STR, PAH-26 and PAH-32) in the PAH gene. Thirty-one types of mutations were identified. A total of 84 mutations were identified in 88 alleles (95.45%), in which the most common mutation have been R243Q (21.59%), EX6-96A>G (6.82%), IVS4-1G>A (5.86%) and IVS7+2T>A (5.86%). Most mutations were found in exons 3, 5, 6, 7, 11 and 12. The polymorphism information content (PIC) of these three STR markers was 0.71 (PAH-STR), 0.48 (PAH-26) and 0.40 (PAH-32), respectively. Prenatal diagnosis was performed successfully with the combined method in 47 fetuses of 44 classical phenylketonuria families. Among them, 11 (23.4%) were diagnosed as affected, 24 (51.1%) as carriers, and 12 (25.5%) as unaffected. Prenatal diagnosis can be achieved efficiently and accurately by stratified sequencing of PAH gene and linkage analysis of STR for classical phenylketonuria families.

  6. Intelligence Patterns among Children with High-Functioning Autism, Phenylketonuria, and Childhood Head Injury.

    ERIC Educational Resources Information Center

    Dennis, Maureen; Lockyer, Linda; Lazenby, Anne L.; Donnelly, Ruth E.; Wilkinson, Margaret; Schoonheyt, Wanda

    1999-01-01

    A study compared the Comprehension: Block Design IQ subtest pattern of 8 children with autism and 24 children with developmental and acquired frontal lobe disorders. Found that children with autism showed low social comprehension related to visual spatial ability, a profile which was shared by children with poorly controlled Phenylketonuria. (CR)

  7. Parental Problem-Solving Skills, Stress, and Dietary Compliance in Phenylketonuria.

    ERIC Educational Resources Information Center

    Fehrenbach, Annette M. B.; Peterson, Lizette

    1989-01-01

    Parents of 30 children with phenylketonuria, classified as being in good or poor dietary control, engaged in verbal and written problem-solving situations under conditions of both high and low time-pressure induced stress. Overall, compliant parents gave higher quality verbal and written problem-solving solutions than noncompliant parents.…

  8. The use of parenteral nutrition for the management of PKU patient undergoing chemotherapy for lymphoma: a case report.

    PubMed

    Salvarinova-Zivkovic, R; Hartnett, C; Sinclair, G; Dix, D; Horvath, G; Lillquist, Y; Stockler-Ipsiroglu, S

    2012-04-01

    The metabolic control of phenylalanine levels is a challenge during illness. We present the metabolic management of a 6 year old boy with classical PKU who was diagnosed with stage III intraabdominal Burkit's lymphoma and underwent surgical resection and chemotherapy. The metabolic control during chemotherapy was achieved by the use of parenteral custom made amino acid solution and pro-active adjustment of intake. From the 94 obtained plasma phenylalanine (Phe) levels, 18.4% were above our clinic's recommended upper limit (360 μmol/L, 6 mg/dL) while 52.7% of Phe levels were below the recommended lower limit (120 μmol/L, 2 mg/dL). Phe levels above recommended range were associated with low caloric/protein intake, while levels below recommended range reflected the difficulty in achieving the full prescribed Phe intake. We recommend early institution of custom made amino acid solution with maximum amino acid content and caloric intake to provide optimal phenylalanine control. Administration of phenylalanine via regular intravenous amino acid solution may assist in avoiding low Phe levels when prescribed intake is compromised due to vomiting and other disease related illnesses. Use of custom made, phenylalanine free amino acid solution proved beneficial in the management of blood phenylalanine levels in a PKU patient during chemotherapy for Burkitt lymphoma.

  9. Visual functions in phenylketonuria-evaluating the dopamine and long-chain polyunsaturated fatty acids depletion hypotheses.

    PubMed

    Gramer, Gwendolyn; Förl, Birgit; Springer, Christina; Weimer, Petra; Haege, Gisela; Mackensen, Friederike; Müller, Edith; Völcker, Hans Eberhard; Hoffmann, Georg Friedrich; Lindner, Martin; Krastel, Hermann; Burgard, Peter

    2013-01-01

    In phenylketonuria presymptomatic treatment following newborn screening prevents severe mental and physical impairment. The reasons for subtle impairments of cerebral functions despite early treatment remain unclear. We assessed a broad spectrum of visual functions in early-treated patients with phenylketonuria and evaluated two hypotheses-the dopamine and the long-chain polyunsaturated fatty acids (LCPUFAs) depletion hypotheses. Contrast sensitivity, colour vision, electroretinography, frequency doubling technology campimetry (FDT), and their relation with blood phenylalanine and docosahexaenoic acid levels were assessed in 36 patients with phenylketonuria and 18 age-matched healthy controls. Contrast sensitivity was significantly lower and total error scores in colour vision significantly higher in patients than controls. Electroretinography results differed significantly between patients and controls. We found a trend for the effect of phenylalanine-levels on contrast sensitivity and a significant effect on colour vision/FDT results. Docosahexaenoic acid levels in erythrocytes were not associated with visual functions. This is the first evaluation of visual functions in phenylketonuria using a comprehensive ophthalmological test battery. We found no evidence supporting the long-chain polyunsaturated fatty acids depletion hypothesis. However, the effect of phenylalanine-levels on visual functions suggests that imbalance between phenylalanine and tyrosine may affect retinal dopamine levels in phenylketonuria. This is supported by the similar patterns of visual functions in patients with phenylketonuria observed in our study and patients with Parkinson's disease. Copyright © 2012 Elsevier Inc. All rights reserved.

  10. Neonatal Screening Tests.

    ERIC Educational Resources Information Center

    Vigue, Charles L.

    1986-01-01

    Describes several laboratory experiments that are adaptations of clinical tests for certain genetic diseases in babies. Information and procedures are provided for tests for phenylketonuria (PKU), galactosemia, tyrosinemia, cystinuria, and mucopolysaccharidosis. Discusses the effects of each disease on the infants' development. (TW)

  11. Neonatal Screening Tests.

    ERIC Educational Resources Information Center

    Vigue, Charles L.

    1986-01-01

    Describes several laboratory experiments that are adaptations of clinical tests for certain genetic diseases in babies. Information and procedures are provided for tests for phenylketonuria (PKU), galactosemia, tyrosinemia, cystinuria, and mucopolysaccharidosis. Discusses the effects of each disease on the infants' development. (TW)

  12. Long-term developmental progression in infants and young children taking sapropterin for phenylketonuria: a two-year analysis of safety and efficacy.

    PubMed

    Longo, Nicola; Siriwardena, Komudi; Feigenbaum, Annette; Dimmock, David; Burton, Barbara K; Stockler, Sylvia; Waisbren, Susan; Lang, William; Jurecki, Elaina; Zhang, Charlie; Prasad, Suyash

    2015-05-01

    Sapropterin is an oral synthetic formulation of tetrahydrobiopterin prescribed as adjunctive therapy for phenylketonuria. The efficacy of sapropterin in reducing blood phenylalanine levels has been demonstrated in clinical studies of individuals with phenylketonuria older than 4 years of age. Its effect on neurocognitive functioning in younger children has not been examined. A 2-year interim analysis of blood phenylalanine levels, prescribed dietary phenylalanine intake, and neurocognitive functioning was performed in children who started receiving sapropterin at 0-6 years of age and responded with a ≥30% mean blood phenylalanine reduction. Children were evaluated at baseline and 2-year follow-up. Sapropterin had a favorable safety profile and lowered blood phenylalanine levels with increased prescribed dietary phenylalanine intakes. Mean full-scale intelligence quotient was 103 ± 12 at baseline and 104 ± 10 at 2-year follow-up (P = 0.50, paired t-test, n = 25). For children younger than 30 months of age, the cognitive composite score from the Bayley Scales of Infant and Toddler Development, Third Edition, remained within the average range. Sapropterin had a favorable safety profile, was effective in lowering blood phenylalanine levels while clinically requiring dietary adjustment, resulting in increased phenylalanine intake, and preserved neurocognitive performance in children who started therapy between 0 and 6 years of age.

  13. Glycomacropeptide for nutritional management of phenylketonuria: a randomized, controlled, crossover trial.

    PubMed

    Ney, Denise M; Stroup, Bridget M; Clayton, Murray K; Murali, Sangita G; Rice, Gregory M; Rohr, Frances; Levy, Harvey L

    2016-08-01

    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. 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. 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. 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. 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

  14. Glycomacropeptide for nutritional management of phenylketonuria: a randomized, controlled, crossover trial12

    PubMed Central

    Stroup, Bridget M; Clayton, Murray K; Murali, Sangita G; Rice, Gregory M; Rohr, Frances; Levy, Harvey L

    2016-01-01

    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

  15. Comparison of atherogenic risk factors among poorly controlled and well-controlled adolescent phenylketonuria patients.

    PubMed

    Gündüz, Mehmet; Çakar, Sevim; Kuyum, Pınar; Makay, Balahan; Arslan, Nur

    2016-06-01

    Previous studies investigating the known risk factors of atherosclerosis in phenylketonuria patients have shown conflicting results. The primary aim of our study was to investigate the serum atherogenic markers in adolescent classical phenylketonuria patients and compare these parameters with healthy peers. The secondary aim was to compare these atherogenic markers in well-controlled and poorly controlled patients. A total of 59 patients (median age: 12.6 years, range: 11-17 years) and 44 healthy controls (median age: 12.0 years, range: 11-15 years) were enrolled in our study. Phenylketonuria patients were divided into two groups: well-controlled (serum phenylalanine levels below 360 µmol/L; 24 patients) and poorly controlled patients (serum phenylalanine levels higher than 360 µmol/L). The mean high-density lipoprotein cholesterol levels of well-controlled patients (1.0±0.2 mmol/L) were significantly lower compared with poorly controlled patients and controls (1.1±0.2 mmol/L, p=0.011 and 1.4±0.2 mmol/L, p<0.001, respectively). Poorly controlled patients had lower high-density lipoprotein cholesterol levels than healthy controls (p=0.003). Homocysteine levels of both well-controlled (9.8±6.4 µmol/L) and poorly controlled (9.2±5.6 µmol/L) patients were higher compared with controls (5.8±1.8 µmol/L, p<0.01). The mean platelet volume of well-controlled patients (9.5±1.1 fL) was higher than that of poorly controlled patients and controls (8.9±0.8 fL, p=0.024 and 7.7±0.6 fL, p<0.001, respectively). Lower high-density lipoprotein cholesterol and higher homocysteine and mean platelet volume levels were detected in phenylketonuria patients. In particular, these changes were more prominent in well-controlled patients. We conclude that phenylketonuria patients might be at risk for atherosclerosis, and therefore screening for atherosclerotic risk factors should be included in the phenylketonuria therapy and follow-up in addition to other parameters.

  16. Mapping the functional landscape of frequent phenylalanine hydroxylase (PAH) genotypes promotes personalised medicine in phenylketonuria.

    PubMed

    Danecka, Marta K; Woidy, Mathias; Zschocke, Johannes; Feillet, François; Muntau, Ania C; Gersting, Søren W

    2015-03-01

    In phenylketonuria, genetic heterogeneity, frequent compound heterozygosity, and the lack of functional data for phenylalanine hydroxylase genotypes hamper reliable phenotype prediction and individualised treatment. 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. 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. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  17. Long-chain polyunsaturated fatty acid status in children, adolescents and adults with phenylketonuria.

    PubMed

    Gramer, Gwendolyn; Haege, Gisela; Langhans, Claus-Dieter; Schuhmann, Vera; Burgard, Peter; Hoffmann, Georg F

    2016-06-01

    Patients with phenylketonuria have been reported to be deficient in long-chain polyunsaturated fatty acids (LCPUFAs). It has been postulated that good compliance with the dietary regimen negatively influences LCPUFA status. In 36 patients with phenylketonuria and 18 age-matched healthy control subjects LCPUFA-levels in plasma phospholipids and cholesteryl esters, erythrocyte phosphatidylcholine and phosphatidylethanolamine were evaluated. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels did not differ significantly between patients and control subjects in plasma and erythrocyte fractions. There was a significant negative correlation between SDS (standard deviation) scores of DHA-levels in erythrocyte parameters from the respective age-matched control group and patients' concurrent and long-term phenylalanine levels for erythrocyte phosphatidylethanolamine and erythrocyte phosphatidylcholine. Patients with lower (higher) phenylalanine levels had positive (negative) DHA-SDS. In contrast to previous reports we did not find lower LCPUFA-levels in patients with phenylketonuria compared to age-matched healthy control subjects. Good dietary control was associated with better LCPUFA status. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Linking genotypes database with locus-specific database and genotype-phenotype correlation in phenylketonuria.

    PubMed

    Wettstein, Sarah; Underhaug, Jarl; Perez, Belen; Marsden, Brian D; Yue, Wyatt W; Martinez, Aurora; Blau, Nenad

    2015-03-01

    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.

  19. Serum phenylalanine screening

    MedlinePlus

    ... test to look for signs of the disease phenylketonuria (PKU). The test detects abnormally high levels of ... A.M. Editorial team. Newborn Screening Read more Phenylketonuria Read more Latest Health News Read more A. ...

  20. CW/Pulsed H- ion beam generation with PKU Cs-free 2.45 GHz microwave driven ion source

    NASA Astrophysics Data System (ADS)

    Peng, S. X.; Ren, H. T.; Xu, Y.; Zhang, T.; Zhang, A. L.; Zhang, J. F.; Zhao, J.; Guo, Z. Y.; Chen, J. E.

    2015-04-01

    Circular accelerators used for positron emission tomography (PET, i.e. accelerator used for make radio isotopes) need several mA of CW H- ion beam for their routine operation. Other facilities, like Space Radio-Environment Simulate Assembly (SPRESA), require less than 10 mA pulsed mode H- beam. Caesium free negative hydrogen ion source is a good choice for those facilities because of its compact structure, easy operation and low cost. Up to now, there is no H- source able to produce very intense H- beams with important variation of the duty factor[1]. Recently, a new version of 2.45 GHz microwave H- ion source was designed at PKU, based on lessons learnt from the previous one. This non cesiated source is very compact thanks to its permanent magnet configuration. Special attention was paid on the design of the discharge chamber structure, electron dumping and extraction system. Source test to produce H- ion beams in pulsed and CW mode was carried out on PKU ion source test bench. In CW mode, a 10.8 mA/30keV H- beam with rms emittance about 0.16 π.mm.mrad has been obtained with only 500 W rf power. The power efficiency reaches 21 mA/kW. In pulsed mode with duty factor of 10% (100Hz/1ms), this compact source can easily deliver 20 mA H- ion beam at 35 keV with rms emittance about 0.2 π.mm.mrad when RF power is set at 2.2 kW (peak power). Several hour successive running operation in both modes and totaling more than 200 hours proves its high quality. The outside dimension of this new H- source body is ϕ116 mm × 124 mm, and the entire H- source infrastructure, including rf matching section, plasma chamber and extraction system, is ϕ310 × 180 mm. The high voltage region is limited with in a ϕ310 mm × 230 mm diagram. Details are given in this paper.

  1. Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial.

    PubMed

    Longo, Nicola; Harding, Cary O; Burton, Barbara K; Grange, Dorothy K; Vockley, Jerry; Wasserstein, Melissa; Rice, Gregory M; Dorenbaum, Alejandro; Neuenburg, Jutta K; Musson, Donald G; Gu, Zhonghua; Sile, Saba

    2014-07-05

    Phenylketonuria is an inherited disease caused by impaired activity of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine, leading to accumulation of phenylalanine and subsequent neurocognitive dysfunction. Phenylalanine ammonia lyase is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. We aimed to assess the safety, tolerability, pharmacokinetic characteristics, and efficacy of recombinant Anabaena variabilis phenylalanine ammonia lyase (produced in Escherichia coli) conjugated with polyethylene glycol (rAvPAL-PEG) in reducing phenylalanine concentrations in adult patients with phenylketonuria. In this open-label, phase 1, multicentre trial, single subcutaneous injections of rAvPAL-PEG were given in escalating doses (0·001, 0·003, 0·010, 0·030, and 0·100 mg/kg) to adults with phenylketonuria. Participants aged 18 years or older with blood phenylalanine concentrations of 600 μmol/L or higher were recruited from among patients attending metabolic disease clinics in the USA. The primary endpoints were safety and tolerability of rAvPAL-PEG. Secondary endpoints were the pharmacokinetic characteristics of the drug and its effect on concentrations of phenylalanine. Participants and investigators were not masked to assigned dose group. This study is registered with ClinicalTrials.gov, number NCT00925054. 25 participants were recruited from seven centres between May 6, 2008, and April 15, 2009, with five participants assigned to each escalating dose group. All participants were included in the safety population. The most frequently reported adverse events were injection-site reactions and dizziness, which were self-limited and without sequelae. Two participants had serious adverse reactions to intramuscular medroxyprogesterone acetate, a drug that contains polyethylene glycol as an excipient. Three of five participants given the highest dose of rAvPAL-PEG (0·100 mg/kg) developed a generalised skin rash

  2. Accuracy of six anthropometric skinfold formulas versus air displacement plethysmography for estimating percent body fat in female adolescents with phenylketonuria.

    PubMed

    Douglas, Teresa D; Kennedy, Mary J; Quirk, Meghan E; Yi, Sarah H; Singh, Rani H

    2013-01-01

    The reliability of studies investigating biological and therapeutic factors that influence body composition in PKU patients depends on accurate anthropometric measurements. To determine the precision of six anthropometric skinfold equations versus air displacement plethysmography (ADP) for predicting body fat (BF) percentage in female adolescents with PKU. Skinfold and ADP measurements were recorded from a cross section of 59 female patients with PKU, ages 10-19 years. Anthropometric measures were used to calculate percent BF using equations published by Peterson et al., Loftin et al. (TAAG), Slaughter et al., Wilmore and Behnke, Durnin and Womersley, and Jackson et al. Bland-Altman agreement analysis and Lin's concordance correlation coefficient (ρ c) were used to determine the precision of each equation compared with percent BF determined by ADP. Adolescent females with PKU had a mean BF content of 33% measured by ADP, with an inverse association to birth cohort (r = -0.3, P = 0.016). Based on the Bland-Altman method for evaluating agreement, only Peterson's equation did not differ significantly from ADP percent BF results (P = 0.23). Peterson's skinfold equation yielded percent BF estimates with the smallest mean difference from ADP and the smallest standard deviation (0.76 ± 4.8), whereas Slaughter's equation had the largest (-7.7 ± 7.4). Loftin's TAAG equation had the least mean percent error (2.2%), while Slaughter's equation had the highest (19%). Both TAAG and Peterson's equations had the highest concordance correlation coefficients (ρ c = 0.8, ρ c = 0.8), while Slaughter's equation had the lowest (ρ c = 0.3). Peterson's equation is a precise surrogate for ADP when estimating percent BF in female adolescents with PKU, though Loftin's TAAG equation is also effective. Observed decreases in adiposity correlating with birth cohort could reflect steady improvements in patient nutrition care.

  3. Transcultural pediatrics: compliance and outcome of phenylketonuria patients from families with an immigration background.

    PubMed

    Ipsiroglu, Osman S; Herle, Marion; Spoula, Elisabeth; Möslinger, Dorothea; Wimmer, Banu; Burgard, Peter; Bode, Harald; Stöckler-Ipsiroglu, Sylvia

    2005-08-01

    Living in a foreign country with a different lifestyle and a different orientation is a many-faceted challenge for immigrants. A considerable percentage (30-50%) of patients with metabolic disease come from immigrant families from Turkey and the Middle East. Phenylketonuria is one example of metabolic disease in which severe mental retardation can be entirely prevented by early detection via newborn screening and consistent dietary treatment. We report 7 phenylketonuria patients from 3 Turkish families who had considerable difficulty in coping with the diagnosis and adherence to the diet. Blood phenylalanine levels beyond recommended limits and IQ values below average, clearly demonstrate the risks arising from language as well as psychological and cultural communication barriers, despite standardized follow-up care structures and the observance of continuity by medical caregivers. To propose a basis for systematic improvement in the care of patients from immigrant families we suggest that a) the services of professional interpreters be used in case of language barriers; b) social workers with appropriate sociocultural and language competence should accompany the family in a professional manner; c) it would be meaningful to introduce treatment contracts that clearly establish the limits of the client's rights and duties as well as those of the care-givers. From the viewpoint of legislation, providing medical information is duty of the hospital and the use of translator is mandatory with patients from foreign countries and with foreign languages.

  4. [Effects of Different Pretreatment Methods on the Phenylketonuria Screening Model by FTIR/ATR Spectroscopy].

    PubMed

    Wang, Wei-wei; Wei, Wei-wei; Song, Xiang-gang; Cheng, Ya-ting; Chen, Chao; Wang, Shu-mei; Liang, Sheng-wang

    2015-05-01

    To establish a phenylketonuria screening model by FTIR/ATR spectroscopy, and to compare the effects of different pretreatment methods, such as baseline correction, smoothing, derivation, Fourier deconvolution, on the model quality. A consensus partial least squares regression method (cPLS) was used to build the quantitative model of phenylalanine in dried blood spots. The effects of different pretreatment methods on the model performance were investigated, using the correlation coefficient (r), root mean square error of prediction (RMSEP), mean relative error (MRE) and predictive accuracy (Acc). The nine-point smoothing coupled with the first differential was found to perform the best. Compared with the model by the original spectra, its r, RMSEP, MRE and Acc were improved from 0. 822 7, 115. 8, 0. 395 and 94. 6 to 0. 889 9, 102. 2, 0. 286 and 100, respectively. With the advantages of fast speed, easy process, no reagents consumption and environmental protection, the present method is expected to become a simple and green technology for rapidly screening the neonatal phenylketonuria in a large population.

  5. Phenylketonuria, congenital hypothyroidism and haemoglobinopathies: public health issues for a Brazilian newborn screening program.

    PubMed

    Botler, Judy; Camacho, Luiz Antonio Bastos; Cruz, Marly Marques da

    2012-09-01

    In this study, the frequency of detected congenital hypothyroidism, phenylketonuria and haemoglobinopathies in the State of Rio de Janeiro's (Brazil) Newborn Screening Program (NBSP) was analyzed between the years of 2005 and 2007. There were two Newborn Screening Reference Centers (named NSRC A and B) with programmatic differences. In 2007, overall detection coverage reached 80.7%. The increase in the incidence of congenital hypothyroidism (1:1,030 in 2007) was attributed to the reduction of neonatal TSH value limits over time. The incidence discrepancy of phenylketonuria between NSRC A (1:28,427) and B (1:16,522) might be partially explained by the small number of cases. The incidence of sickle cell disease and its traits were uniformly high (1:1,288 and 1:21, respectively). This was coherent with the ethnic composition of the population. The differences in laboratory methods and critical values, in addition to other programmatic issues, may explain the variances in the results and limited analysis of the role of biological and environmental determinants in the occurrence of these diseases.

  6. Selective activity of phenylacetate against malignant gliomas: resemblance to fetal brain damage in phenylketonuria.

    PubMed

    Samid, D; Ram, Z; Hudgins, W R; Shack, S; Liu, L; Walbridge, S; Oldfield, E H; Myers, C E

    1994-02-15

    Phenylacetate, a deaminated metabolite of phenylalanine, has been implicated in damage to immature brain in phenylketonuria. Because primary brain tumors are highly reminiscent of the immature central nervous system, these neoplasms should be equally vulnerable. We show here that sodium phenylacetate can induce cytostasis and reversal of malignant properties of cultured human glioblastoma cells, when used at pharmacological concentrations that are well tolerated by children and adults. Treated tumor cells exhibited biochemical alterations similar to those observed in phenylketonuria-like conditions, including selective decline in de novo cholesterol synthesis from mevalonate. Because gliomas, but not mature normal brain cells, are highly dependent on mevalonate for production of sterols and isoprenoids vital for cell growth, sodium phenylacetate would be expected to affect tumor growth in vivo while sparing normal tissues. Systemic treatment of rats bearing intracranial gliomas resulted in significant tumor suppression with no apparent toxicity to the host. The data indicate that phenylacetate, acting through inhibition of protein prenylation and other mechanisms, may offer a safe and effective novel approach to treatment of malignant gliomas and perhaps other neoplasms as well.

  7. Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness.

    PubMed

    Jeannesson-Thivisol, Elise; Feillet, François; Chéry, Céline; Perrin, Pascal; Battaglia-Hsu, Shyue-Fang; Herbeth, Bernard; Cano, Aline; Barth, Magalie; Fouilhoux, Alain; Mention, Karine; Labarthe, François; Arnoux, Jean-Baptiste; Maillot, François; Lenaerts, Catherine; Dumesnil, Cécile; Wagner, Kathy; Terral, Daniel; Broué, Pierre; de Parscau, Loïc; Gay, Claire; Kuster, Alice; Bédu, Antoine; Besson, Gérard; Lamireau, Delphine; Odent, Sylvie; Masurel, Alice; Guéant, Jean-Louis; Namour, Fares

    2015-12-15

    Mutations in Phenylalanine Hydroxylase (PAH) gene cause phenylketonuria. Sapropterin (BH4), the enzyme cofactor, is an important therapeutical strategy in phenylketonuria. However, PAH is a highly polymorphic gene and it is difficult to identify BH4-responsive genotypes. We seek here to improve prediction of BH4-responsiveness through comparison of genotypes, BH4-loading test, predictions of responsiveness according to the literature and types and locations of mutations. A total of 364 French patients among which, 9 % had mild hyperphenylalaninemia, 17.7 % mild phenylketonuria and 73.1 % classical phenylketonuria, benefited from a 24-hour BH4-loading test and had the PAH gene sequenced and analyzed by Multiplex Ligation Probe Amplification. Overall, 31.6 % of patients were BH4-responsive. The number of different mutations found was 127, including 26 new mutations. The mutations c.434A > T, c.500A > T, c.529G > C, c.1045 T > G and c.1196 T > C were newly classified as being BH4-responsive. We identified 261 genotypes, among which 46 were newly recognized as being BH4-responsive. Even though patients carry 2 responsive alleles, BH4-responsiveness cannot be predicted with certainty unless they present mild hyperphenylalaninemia. BH4-responsiveness cannot be predicted in patients carrying one responsive mutation only. In general, the milder the phenotype is, the stronger the BH4-response is. Almost exclusively missense mutations, particularly in exons 12, 11 and 8, are associated with BH4-responsiveness and any other type of mutation predicts a negative response. This study is the first of its kind, in a French population, to identify the phenotype associated with several combinations of PAH mutations. As others, it highlights the necessity of performing simultaneously BH4 loading test and molecular analysis in monitoring phenylketonuria patients.

  8. Melatonin and dopamine as biomarkers to optimize treatment in phenylketonuria: effects of tryptophan and tyrosine supplementation.

    PubMed

    Yano, Shoji; Moseley, Kathryn; Azen, Colleen

    2014-07-01

    To determine whether additional supplementation of tryptophan (Trp) and tyrosine (Tyr) improve serotonin and dopamine metabolism in individuals with phenylketonuria treated with large neutral amino acid (LNAA) tablets. Ten adult individuals with phenylketonuria participated in a randomized, double-blind, placebo-controlled cross-over study consisting of three 3-week phases: washout, treatment with LNAA tablets plus supplementation with either Trp and Tyr tablets or placebo, and LNAA tablets plus the alternate supplementation. An overnight protocol to measure blood melatonin, a serotonin metabolite in the pinealocytes, and urine 6-sulfatoxymelatonin and dopamine in first-void urine specimens was conducted after each phase. Serum melatonin and urine 6-sulfatoxymelatonin and dopamine levels were increased in the LNAA phase (LNAA plus placebo) compared with the washout phase. Serum melatonin and urine 6-sulfatoxymelatonin were not increased in the active phase (LNAA plus Trp + Tyr) compared with the LNAA phase, although plasma Trp:LNAA was increased compared with the LNAA phase. Among 7 subjects with a plasma Trp/LNAA >0.03, a negative correlation between urine 6-sulfatoxymelatonin and plasma phenylalanine levels was observed (r = -0.072). Urine dopamine levels and plasma Tyr:LNAA were increased in the active phase compared with the LNAA phase. Melatonin levels were not increased with the higher dose of Trp supplementation, but dopamine levels were increased with the higher dose of Tyr supplementation. Serotonin synthesis appears to be suppressed by high phenylalanine levels at the Trp hydroxylase level. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Therapeutic implication of L-phenylalanine aggregation mechanism and its modulation by D-phenylalanine in phenylketonuria

    PubMed Central

    Singh, Virender; Rai, Ratan Kumar; Arora, Ashish; Sinha, Neeraj; Thakur, Ashwani Kumar

    2014-01-01

    Self-assembly of phenylalanine is linked to amyloid formation toxicity in phenylketonuria disease. We are demonstrating that L-phenylalanine self-assembles to amyloid fibrils at varying experimental conditions and transforms to a gel state at saturated concentration. Biophysical methods including nuclear magnetic resonance, resistance by alpha-phenylglycine to fibril formation and preference of protected phenylalanine to self-assemble show that this behaviour of L-phenylalanine is governed mainly by hydrophobic interactions. Interestingly, D-phenylalanine arrests the fibre formation by L-phenylalanine and gives rise to flakes. These flakes do not propagate further and prevent fibre formation by L-phenylalanine. This suggests the use of D-phenylalanine as modulator of L-phenylalanine amyloid formation and may qualify as a therapeutic molecule in phenylketonuria. PMID:24464217

  10. Neuropsychological Deficits in Early Treated Phenylketonuric Children.

    ERIC Educational Resources Information Center

    Pennington, Bruce F.; And Others

    1985-01-01

    Six early treated children with phenylketonuria (PKU) were compared at 9 to 14 years of age on a neuropsychological measure with three groups of children with documented neurological disorders. PKU Ss had overall level of neuropsychological impairment similar to that of brain-damaged groups. PKU Ss did not show consistent pattern of…

  11. Neuropsychological Deficits in Early Treated Phenylketonuric Children.

    ERIC Educational Resources Information Center

    Pennington, Bruce F.; And Others

    1985-01-01

    Six early treated children with phenylketonuria (PKU) were compared at 9 to 14 years of age on a neuropsychological measure with three groups of children with documented neurological disorders. PKU Ss had overall level of neuropsychological impairment similar to that of brain-damaged groups. PKU Ss did not show consistent pattern of…

  12. White matter integrity and executive abilities following treatment with tetrahydrobiopterin (BH4) in individuals with phenylketonuria.

    PubMed

    White, Desirée A; Antenor-Dorsey, Jo Ann V; Grange, Dorothy K; Hershey, Tamara; Rutlin, Jerrel; Shimony, Joshua S; McKinstry, Robert C; Christ, Shawn E

    2013-11-01

    Tetrahydrobiopterin (BH(4)) lowers blood phenylalanine (Phe) in individuals with PKU who are responders, but its effects on the brain and cognition have not been explored thoroughly. We examined blood Phe, microstructural white matter integrity, and executive abilities in 12 BH(4) responders before (i.e., baseline) and after (i.e., follow-up) six months of treatment with BH(4). Compared with baseline, Phe in these responders decreased by 51% during a 4 week screening period after initiation of treatment and remained lowered by 37% over the 6 month follow-up period. Significant improvements in white matter integrity, evaluated by mean diffusivity from diffusion tensor imaging, were also found following six months of treatment. Improvements in executive abilities were not identified, although six months may have been a period too brief for changes in cognition to follow changes in the brain. To our knowledge, our study is the first to explore relationships among Phe, white matter integrity, executive abilities, and BH(4) treatment within a single study. © 2013.

  13. Phenylketonuria: protein content and amino acids profile of dishes for phenylketonuric patients. The relevance of phenylalanine.

    PubMed

    Pimentel, Filipa B; Alves, Rita C; Costa, Anabela S G; Torres, Duarte; Almeida, Manuela F; Oliveira, M Beatriz P P

    2014-04-15

    Phenylketonuria is an inborn error of metabolism, involving, in most cases, a deficient activity of phenylalanine hydroxylase. Neonatal diagnosis and a prompt special diet (low phenylalanine and natural-protein restricted diets) are essential to the treatment. The lack of data concerning phenylalanine contents of processed foodstuffs is an additional limitation for an already very restrictive diet. Our goals were to quantify protein (Kjeldahl method) and amino acid (18) content (HPLC/fluorescence) in 16 dishes specifically conceived for phenylketonuric patients, and compare the most relevant results with those of several international food composition databases. As might be expected, all the meals contained low protein levels (0.67-3.15 g/100 g) with the highest ones occurring in boiled rice and potatoes. These foods also contained the highest amounts of phenylalanine (158.51 and 62.65 mg/100 g, respectively). In contrast to the other amino acids, it was possible to predict phenylalanine content based on protein alone. Slight deviations were observed when comparing results with the different food composition databases. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. A novel common large genomic deletion and two new missense mutations identified in the Romanian phenylketonuria population.

    PubMed

    Gemperle-Britschgi, Corinne; Iorgulescu, Daniela; Mager, Monica Alina; Anton-Paduraru, Dana; Vulturar, Romana; Thöny, Beat

    2016-01-15

    The mutation spectrum for the phenylalanine hydroxylase (PAH) gene was investigated in a cohort of 84 hyperphenylalaninemia (HPA) patients from Romania identified through newborn screening or neurometabolic investigations. Differential diagnosis identified 81 patients with classic PAH deficiency while 3 had tetrahydropterin-cofactor deficiency and/or remained uncertain due to insufficient specimen. PAH-genetic analysis included a combination of Sanger sequencing of exons and exon–intron boundaries, MLPA and NGS with genomic DNA, and cDNA analysis from immortalized lymphoblasts. A diagnostic efficiency of 99.4% was achieved, as for one allele (out of a total of 162 alleles) no mutation could be identified. The most prevalent mutation was p.Arg408Trp which was found in ~ 38% of all PKU alleles. Three novel mutations were identified, including the two missense mutations p.Gln226Lys and p.Tyr268Cys that were both disease causing by prediction algorithms, and the large genomic deletion EX6del7831 (c.509 + 4140_706 + 510del7831) that resulted in skipping of exon 6 based on PAH-cDNA analysis in immortalized lymphocytes. The genomic deletion was present in a heterozygous state in 12 patients, i.e. in ~ 8% of all the analyzed PKU alleles, and might have originated from a Romanian founder.

  15. Prolonged exposure to high and variable phenylalanine levels over the lifetime predicts brain white matter integrity in children with phenylketonuria.

    PubMed

    Hood, Anna; Antenor-Dorsey, Jo Ann V; Rutlin, Jerrel; Hershey, Tamara; Shimony, Joshua S; McKinstry, Robert C; Grange, Dorothy K; Christ, Shawn E; Steiner, Robert; White, Desiree A

    2015-01-01

    In this study, we retrospectively examined the microstructural white matter integrity of children with early- and continuously-treated PKU (N=36) in relation to multiple indices of phenylalanine (Phe) control over the lifetime. White matter integrity was assessed using mean diffusivity (MD) from diffusion tensor imaging (DTI). Eight lifetime indices of Phe control were computed to reflect average Phe (mean, index of dietary control), variability in Phe (standard deviation, standard error of estimate, % spikes), change in Phe with age (slope), and prolonged exposure to Phe (mean exposure, standard deviation exposure). Of these indices, mean Phe, mean exposure, and standard deviation exposure were the most powerful predictors of widespread microstructural white matter integrity compromise. Findings from the two previously unexamined exposure indices reflected the accumulative effects of elevations and variability in Phe. Given that prolonged exposure to elevated and variable Phe was particularly detrimental to white matter integrity, Phe should be carefully monitored and controlled throughout childhood, without liberalization of Phe control as children with PKU age.

  16. CW/Pulsed H{sup −} ion beam generation with PKU Cs-free 2.45 GHz microwave driven ion source

    SciTech Connect

    Peng, S. X. Ren, H. T.; Xu, Y.; Zhang, T.; Zhang, J. F.; Zhao, J.; Guo, Z. Y.; Zhang, A. L.; Chen, J. E.

    2015-04-08

    Circular accelerators used for positron emission tomography (PET, i.e. accelerator used for make radio isotopes) need several mA of CW H- ion beam for their routine operation. Other facilities, like Space Radio-Environment Simulate Assembly (SPRESA), require less than 10 mA pulsed mode H{sup −} beam. Caesium free negative hydrogen ion source is a good choice for those facilities because of its compact structure, easy operation and low cost. Up to now, there is no H{sup −} source able to produce very intense H{sup −} beams with important variation of the duty factor{sup [1]}. Recently, a new version of 2.45 GHz microwave H{sup −} ion source was designed at PKU, based on lessons learnt from the previous one. This non cesiated source is very compact thanks to its permanent magnet configuration. Special attention was paid on the design of the discharge chamber structure, electron dumping and extraction system. Source test to produce H{sup −} ion beams in pulsed and CW mode was carried out on PKU ion source test bench. In CW mode, a 10.8 mA/30keV H{sup −} beam with rms emittance about 0.16 π·mm·mrad has been obtained with only 500 W rf power. The power efficiency reaches 21 mA/kW. In pulsed mode with duty factor of 10% (100Hz/1ms), this compact source can easily deliver 20 mA H{sup −} ion beam at 35 keV with rms emittance about 0.2 π·mm·mrad when RF power is set at 2.2 kW (peak power). Several hour successive running operation in both modes and totaling more than 200 hours proves its high quality. The outside dimension of this new H{sup −} source body is ϕ116 mm × 124 mm, and the entire H{sup −} source infrastructure, including rf matching section, plasma chamber and extraction system, is ϕ310 × 180 mm. The high voltage region is limited with in a ϕ310 mm × 230 mm diagram. Details are given in this paper.

  17. Tetrahydrobiopterin responsiveness in phenylketonuria: prediction with the 48-hour loading test and genotype

    PubMed Central

    2013-01-01

    Background How to efficiently diagnose tetrahydrobiopterin (BH4) responsiveness in patients with phenylketonuria remains unclear. This study investigated the positive predictive value (PPV) of the 48-hour BH4 loading test and the additional value of genotype. Methods Data of the 48-hour BH4 loading test (20 mg BH4/kg/day) were collected at six Dutch university hospitals. Patients with ≥30% phenylalanine reduction at ≥1 time points during the 48 hours (potential responders) were invited for the BH4 extension phase, designed to establish true-positive BH4 responsiveness. This is defined as long-term ≥30% reduction in mean phenylalanine concentration and/or ≥4 g/day and/or ≥50% increase of natural protein intake. Genotype was collected if available. Results 177/183 patients successfully completed the 48-hour BH4 loading test. 80/177 were potential responders and 67/80 completed the BH4 extension phase. In 58/67 true-positive BH4 responsiveness was confirmed (PPV 87%). The genotype was available for 120/177 patients. 41/44 patients with ≥1 mutation associated with long-term BH4 responsiveness showed potential BH4 responsiveness in the 48-hour test and 34/41 completed the BH4 extension phase. In 33/34 true-positive BH4 responsiveness was confirmed. 4/40 patients with two known putative null mutations were potential responders; 2/4 performed the BH4 extension phase but showed no true-positive BH4 responsiveness. Conclusions The 48-hour BH4 loading test in combination with a classified genotype is a good parameter in predicting true-positive BH4 responsiveness. We propose assessing genotype first, particularly in the neonatal period. Patients with two known putative null mutations can be excluded from BH4 testing. PMID:23842451

  18. The neonatal tetrahydrobiopterin loading test in phenylketonuria: what is the predictive value?

    PubMed

    Anjema, Karen; Hofstede, Floris C; Bosch, Annet M; Rubio-Gozalbo, M Estela; de Vries, Maaike C; Boelen, Carolien C A; van Rijn, Margreet; van Spronsen, Francjan J

    2016-01-29

    It is unknown whether the neonatal tetrahydrobiopterin (BH4) loading test is adequate to diagnose long-term BH4 responsiveness in PKU. Therefore we compared the predictive value of the neonatal (test I) versus the 48-h BH4 loading test (test II) and long-term BH4 responsiveness. Data on test I (>1991, 20 mg/kg) at T = 8 (n = 85) and T = 24 (n = 5) were collected and compared with test II and long-term BH4 responsiveness at later age, with ≥30% Phe decrease used as the cut-off. The median (IQR) age at hospital diagnosis was 9 (7-11) days and the age at test II was 11.8 (6.6-13.7) years. The baseline Phe concentrations at test I were significantly higher compared to test II (1309 (834-1710) versus 514 (402-689) μmol/L, respectively, P = 0.000). 15/85 patients had a positive test I T = 8. All, except one patient who was not tested for long-term BH4 responsiveness, showed long-term BH4 responsiveness. In 20/70 patients with a negative test I T = 8, long-term BH4 responsiveness was confirmed. Of 5 patients with a test I T = 24, 1/5 was positive at both tests and showed long-term BH4 responsiveness, 2/5 had negative results at both tests and 2/5 showed a negative test I T = 24, but a positive test II with 1/2 showing long-term BH4 responsiveness. Both a positive neonatal 8- and 24-h BH4 loading test are predictive for long-term BH4 responsiveness. However, a negative test does not rule out long-term BH4 responsiveness. Other alternatives to test for BH4 responsiveness at neonatal age should be investigated.

  19. CITRIN DEFICIENCY: AN INFANT INCIDENTALLY DETECTED BY PHENYLKETONURIA SCREENING WITH A NOVEL MUTATION IN SLC25A13 GENE.

    PubMed

    Zeybek, A C Aktuglu; Kiykim, E; Zubarioglu, T; Cansever, M S; Ceylaner, S; Erkan, T

    2015-01-01

    We report the first Turkish patient with citrin deficiency detected incidentally by phenylketonuria screening. Mild cholestasis, increased α-fetoprotein level, aminoacidemia including citrulline and coagulation disorder suggested citrin deficiency. Screening the SLC25A13 gene revealed compound heterozygosity harboring a novel mutation, c.851-854delGTAT (p.M285Pfs*2)/ p.I290T (c.869T>C). Progression to type II citrullinemia was considered due to hyperammonemia episodes resulting from high carbohydrate/low protein diet. High protein/low carbohydrate diet resulted in cessation of hyperammonemia episodes, reversal of hepatic dysfunction and steatohepatitis. Our report illustrates the importance of awareness on citrin deficiency.

  20. Heart Murmurs and Your Child (For Parents)

    MedlinePlus

    ... heard before. Heart murmurs are rated on a scale from 1 to 6 based on how loud ... PKU (phenylketonuria, a genetic error of the body's metabolism). Common Heart Defects Several kinds of heart problems ...

  1. Amino Acid Metabolism Disorders

    MedlinePlus

    ... this process. One group of these disorders is amino acid metabolism disorders. They include phenylketonuria (PKU) and maple syrup urine disease. Amino acids are "building blocks" that join together to form ...

  2. Contact with Phenylketonurics and Their Families Beyond Pediatric Age: Conclusion from a Survey and Conference

    ERIC Educational Resources Information Center

    Fisch, Robert O.; And Others

    1977-01-01

    Twenty parents of children 12 years and older with PKU (phenylketonuria, a metabolic disorder which if untreated can result in mental retardation) were surveyed to determine their level of knowledge and their needs. (CL)

  3. Contact with Phenylketonurics and Their Families Beyond Pediatric Age: Conclusion from a Survey and Conference

    ERIC Educational Resources Information Center

    Fisch, Robert O.; And Others

    1977-01-01

    Twenty parents of children 12 years and older with PKU (phenylketonuria, a metabolic disorder which if untreated can result in mental retardation) were surveyed to determine their level of knowledge and their needs. (CL)

  4. Health-related quality of life in children and adolescents with phenylketonuria: unimpaired HRQoL in patients but feared school failure in parents.

    PubMed

    Thimm, Eva; Schmidt, Lisa Elena; Heldt, Katrin; Spiekerkoetter, Ute

    2013-09-01

    Aim of the study was the evaluation of health-related quality of life (HRQoL) and the detection of deviant behavior in early-treated children and adolescents with PKU in comparison with healthy peers. Special focus was laid on the impact of compliance with treatment as defined by the national recommendations on HRQoL. Our investigation in 50 children and adolescents and their parents for the first time demonstrates that despite an overall normal HRQoL in our PKU patient collective, parents are concerned about performance in school especially when phenylalanine concentrations in their children are mainly above the therapeutic range. Adherence to target phenylalanine concentrations ameliorated markedly in patients above 10 years in comparison to younger patients due to relaxed treatment recommendations. Interestingly, this alleged improvement in metabolic control has an impact on the parent assessed but not on the patient assessed appraisal of HRQoL. However, a positive correlation between poor metabolic control and conduct problems was identified by patients' self-assessment. In conclusion, lacking adherence to the strict treatment recommendations in infancy results in significant concern about school success and success in life in parents of PKU patients. With relaxation of dietary phenylalanine restriction at 10 years of age, these concerns diminish.

  5. Long-term treatment with tetrahydrobiopterin in phenylketonuria: treatment strategies and prediction of long-term responders.

    PubMed

    Hennermann, Julia B; Roloff, Sylvia; Gebauer, Christine; Vetter, Barbara; von Arnim-Baas, Annabel; Mönch, Eberhard

    2012-11-01

    Tetrahydrobiopterin (BH4) responsive phenylketonuria has been described more than 10 years ago. However, criteria for the identification of long-term BH4 responsive patients are not yet established. 116 patients with phenylketonuria, aged 4-18 years, were screened for potential long-term BH4 responsiveness by at least two of the following criteria: positive neonatal BH4 loading test, putative BH4 responsive genotype, and/or milder phenotype. Patients had to be on permanent dietary treatment. 23 patients fulfilled these criteria and were tested for long-term BH4 responsiveness: 18/23 were long-term BH4 responsive, 5/23 were not. On long-term BH4 treatment over a period of 48 ± 27 months in a dose of 14.9 ± 3.3mg/kg/day phenylalanine tolerance was increased from 452 ± 201 mg/day to 1593 ± 647 mg/day, corresponding to a mean increase of 1141 ± 528 mg/day. Dietary phenylalanine intake was increased stepwise according to a clear defined protocol. In 8/18 patients, diet was completely liberalized; 10/18 patients still received phenylalanine-free amino acid formula with 0.63 ± 0.23 g/kg/day. The most predictive value for long-term BH4 responsiveness was the combination of pretreatment phenylalanine of < 1200 μmol/L, pretreatment phenylalanine/tyrosine ratio of <15, phenylalanine/tyrosine ratio of <15 on treatment, phenylalanine tolerance of >20mg/kg/day at age 3 years, positive neonatal BH4 loading, and at least one putative BH4 responsive mutation (p = 0.00024). Our data show that long-term BH4 responsiveness may be predicted already during neonatal period by determining maximum pretreatment phenylalanine and phenylalanine/tyrosine concentrations, neonatal BH4 loading and PAH genotype. A clear defined protocol is necessary to install long-term BH4 treatment. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. The Indicator Amino Acid Oxidation Method with the Use of l-[1-13C]Leucine Suggests a Higher than Currently Recommended Protein Requirement in Children with Phenylketonuria.

    PubMed

    Turki, Abrar; Ueda, Keiko; Cheng, Barbara; Giezen, Alette; Salvarinova, Ramona; Stockler-Ipsiroglu, Sylvia; Elango, Rajavel

    2017-02-01

    Phenylketonuria is characterized by mutations in the Phe hydroxylase gene that leads to the accumulation of Phe in plasma and the brain. The standard of care for phenylketonuria is nutritional management with dietary restriction of Phe and the provision of sufficient protein and energy for growth and health maintenance. The protein requirement in children with phenylketonuria is empirically determined based upon phenylketonuria nutritional guidelines that are adjusted individually in response to biochemical markers and growth. We determined dietary protein requirements in children with phenylketonuria with the use of the indicator amino acid oxidation (IAAO) technique, with l-[1-(13)C]Leu as the indicator amino acid. Four children (2 males; 2 females) aged 9-18 y with phenylketonuria [mild hyperphenylalanemia (mHPA); 6-10 mg/dL (360-600 μmol/L)] were recruited to participate in ≥7 separate test protein intakes (range: 0.2-3.2 g ⋅ kg(-1) ⋅ d(-1)) with the IAAO protocol with the use of l-[1-(13)C]Leu followed by the collection of breath and urine samples over 8 h. The diets were isocaloric and provided energy at 1.7 times the resting energy expenditure. Protein was provided as a crystalline amino acid mixture based on an egg protein pattern, except Phe and Leu, which were maintained at a constant across intakes. Protein requirement was determined with the use of a 2-phase linear-regression crossover analysis of the rate of l-[1-(13)C]Leu tracer oxidation. The mean protein requirement was determined to be 1.85 g ⋅ kg(-1) ⋅ d(-1) (R(2) = 0.66; 95% CI: 1.37, 2.33). This result is substantially higher than the 2014 phenylketonuria recommendations (1.14-1.33 g ⋅ kg(-1) ⋅ d(-1); based on 120-140% above the current RDA for age). To our knowledge, this is the first study to directly define a quantitative requirement for protein intake in children with mHPA and indicates that current protein recommendations in children with phenylketonuria may be insufficient

  7. Diseases of Phenylalanine Metabolism

    PubMed Central

    Parker, Charles E.

    1979-01-01

    Continuing investigation of the system that hydroxylates phenylalanine to tyrosine has led to new insights into diseases associated with the malfunction of this system. Good evidence has confirmed that phenylketonuria (PKU) is not caused by a simple lack of phenylalanine hydroxylase. Dihydropteridine reductase deficiency as well as defects in biopterin metabolism may also cause the clinical features of phenylketonuria. Furthermore, these diseases do not respond to the standard treatment for phenylketonuria. PMID:388868

  8. Evaluation of trace element and mineral status and related to levels of amino acid in children with phenylketonuria.

    PubMed

    Gok, Fazilet; Ekin, Suat; Dogan, Murat

    2016-07-01

    The aim of the present study was to examine trace elements (Zn, Cu, Mn, Se, Fe, Co, Cr, Ni, Cd, Pb), minerals (Ca, Mg, K), amino acids status in children with phenylketonuria and also whether they were correlated with each other in phenylketonuric patients. It has been found out that the HPA group was significantly lower than the control group with regards to Zn, Se, K, Ca, Mg and Zn/Cr levels (p<0.001, p<0.01, p<0.001, p<0.01, p<0.01 and p<0.001 respectively). In the patients with HPA, significantly strong positive correlations were observed between magnesium and calcium (r=0.791; p=0.001), also, indicates negative significant correlation between the concentrations of magnesium and phenylalanine (r=-0.591; p=0.026). The results of this study showed that, in the HPA group, phenylalanine-Mg relationship found, the presence of disease will in the evaluation of phenylalanine and other amino acids, together with the value of magnesium is required to consider. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Evidence in Latin America of recurrence of V388M, a phenylketonuria mutation with high in vitro residual activity

    SciTech Connect

    Desviat, L.R.; Perez, B.; De Lucca, M.

    1995-08-01

    Phenylketonuria mutation V388M is frequent in the Iberian Peninsula. In vitro, the V388M mutant enzyme has similar immunoreactive protein and phenylalanine hydroxylase mRNA and had 43% residual activity, which correlates well with the mild phenotype exhibited by the homozygous patients. In Spain it has been detected in 5.7% of the mutant alleles and is always associated with haplotype 1.7. This mutation is also present in high frequency in some Latin American countries (Brazil, 9% Chile, 13%). It is interesting that in Chile most of the alleles bearing this mutation carry haplotype 4.3, although in Brazil it is found only on the background of haplotype 1.7. The origin of V388M in Spain on haplotype 1.7 and in Chile on haplotype 4.3 is clearly different. Recurrence is the most plausible explanation, because the mutation involves a CpG dinucleotide, and a recombination event transferring the mutation from haplotype 1 to 4 is unlikely. 29 refs., 2 figs., 3 tabs.

  10. Behavioral and neurochemical characterization of new mouse model of hyperphenylalaninemia.

    PubMed

    Pascucci, Tiziana; Giacovazzo, Giacomo; Andolina, Diego; Accoto, Alessandra; Fiori, Elena; Ventura, Rossella; Orsini, Cristina; Conversi, David; Carducci, Claudia; Leuzzi, Vincenzo; Puglisi-Allegra, Stefano

    2013-01-01

    Hyperphenylalaninemia (HPA) refers to all clinical conditions characterized by increased amounts of phenylalanine (PHE) in blood and other tissues. According to their blood PHE concentrations under a free diet, hyperphenylalaninemic patients are commonly classified into phenotypic subtypes: classical phenylketonuria (PKU) (PHE > 1200 µM/L), mild PKU (PHE 600-1200 µM/L) and persistent HPA (PHE 120-600 µM/L) (normal blood PHE < 120 µM/L). The current treatment for hyperphenylalaninemic patients is aimed to keep blood PHE levels within the safe range of 120-360 µM/L through a PHE-restricted diet, difficult to achieve. If untreated, classical PKU presents variable neurological and mental impairment. However, even mildly elevated blood PHE levels, due to a bad compliance to dietary treatment, produce cognitive deficits involving the prefrontal cortical areas, extremely sensible to PHE-induced disturbances. The development of animal models of different degrees of HPA is a useful tool for identifying the metabolic mechanisms underlying cognitive deficits induced by PHE. In this paper we analyzed the behavioral and biochemical phenotypes of different forms of HPA (control, mild-HPA, mild-PKU and classic-PKU), developed on the base of plasma PHE concentrations. Our results demonstrated that mice with different forms of HPA present different phenotypes, characterized by increasing severity of behavioral symptoms and brain aminergic deficits moving from mild HPA to classical PKU forms. In addition, our data identify preFrontal cortex and amygdala as the most affected brain areas and confirm the highest susceptibility of brain serotonin metabolism to mildly elevated blood PHE.

  11. [Embryofetopathy of the newborn infant of a phenylketonuric mother. A diagnosis not to be missed].

    PubMed

    Farriaux, J P; Dhondt, J L; Largillière, C; Lacombe, A; Valat, S; Puech, F

    1993-01-01

    Children with phenylketonuria (PKU) detected in the neonatal period and who have received the appropriate diet develop normally whatever their sex. However, female PKU patients who, before becoming pregnant, do not take the precaution to follow a diet bringing phenylalanine to "normal levels" (2 to 5 mg in 100 ml of blood) give birth to children presenting with severe embryofoetal damage (e.g. intrauterine growth retardation, microcephaly, mental retardation, various malformations) directly due to their hyperphenylalaninaemia (20 mg or more in 100 ml of blood under a free diet). It is important to know these facts, since the benefits of systematic neonatal PKU detection may be cancelled by this late complication. The therapeutic approach in such cases is a follows: 1. Young women with known PKU must be informed of this risk and how it can be avoided by a preconception therapeutic diet. This means that they must permanently reside in the same geographical area, receive an adequate information at the end of puberty, use and effective contraception method and program their pregnancies preceded by a return to low phenylalanine diet. 2. Doctors must remember that because PKU detection has not become systematic until 1978, PKU girls of child-bearing are remain undetected, that they are not always mentally debilitated and can normally five birth to children with embryofoetal damage. In case of e.g. unexplained intrauterine growth retardation or microcephaly, it is necessary to perform a Guthrie test on the woman, since a prenatal diagnosis may lead to therapeutic abortion, and a postnatal diagnosis to a genetic counselling which will avoid recurrences.(ABSTRACT TRUNCATED AT 250 WORDS)

  12. Inborn errors in metabolism and 4-boronophenylalanine-fructose-based boron neutron capture therapy.

    PubMed

    Laakso, Juha; Ruokonen, Inkeri; Lapatto, Risto; Kallio, Merja

    2003-11-01

    Infusions of boronophenylalanine-fructose complex (BPA-F), at doses up to 900 mg/kg of BPA and 860 mg/kg of fructose, have been used to deliver boron to cancer tissue for boron neutron capture therapy (BNCT). In patients with phenylketonuria (PKU), phenylalanine accumulates, which is harmful in the long run. PKU has been an exclusion criterion for BPA-F-mediated BNCT. Fructose is harmful to individuals with hereditary fructose intolerance (HFI) in amounts currently used in BNCT. The harmful effects are mediated through induction of hypoglycemia and acidosis, which may lead to irreversible organ damage or even death. Consequently, HFI should be added as an exclusion criterion for BNCT if fructose-containing solutions are used in boron carriers. Non-HFI subjects may also develop symptoms, such as gastrointestinal pain, if the fructose infusion rate is high. We therefore recommend monitoring of glucose levels and correcting possible hypoglycemia promptly. Except for some populations with extremely low PKU prevalence, HFI and PKU prevalences are similar, approximately 1 or 2 per 20,000.

  13. Man made disease: clinical manifestations of low phenylalanine levels in an inadequately treated phenylketonuria patient and mouse study.

    PubMed

    Pode-Shakked, Ben; Shemer-Meiri, Lilach; Harmelin, Alon; Stettner, Noa; Brenner, Ori; Abraham, Smadar; Schwartz, Gerard; Anikster, Yair

    2013-01-01

    Phenylalanine (Phe) deficiency and its clinical manifestations have been previously described mostly as sporadic case reports dating back to the 1960's and 1970's. In these reports, low plasma Phe levels were associated with listlessness, eczematous eruptions and failure to gain weight, most often in infants in their first year of life. Herein we describe a 9 month old female patient with known phenylketonuria, who presented with an unusual constellation of symptoms, including severe erythema and desquamation, alopecia, keratomalacia, corneal perforation, failure to thrive and prolonged diarrhea. The diagnostic possibilities of acrodermatitis enteropathica and vitamin deficiencies were ruled out, and further investigation into her medical history led to the conclusion that during the weeks preceding the hospitalization, the patient's diet consisted of the phenylalanine-free medical formula alone, without the addition of a standard infant formula or food as recommended. Subsequently, dietary control of the blood phenylalanine levels brought swift and marked resolution of the dermatological lesions, with renewal of hair growth. Following this experience, and due to the relative paucity of data regarding the clinical manifestations of low serum phenylalanine levels in humans and their putative pathogenetic mechanisms, we sought to further investigate the effects of a phenylalanine-free diet in a mouse study. For this purpose, twenty mice were randomly allocated to receive either a phenylalanine-deficient diet (n=10) or a normal diet (n=10). Weight was measured weekly, and laboratory tests were obtained including complete blood count, electrolyte studies, and phenylalanine and tyrosine levels. Finally, necropsies and histopathological examinations of different tissues were performed in selected mice, either early after diet initiation, late after diet initiation or following re-introduction of normal diets. The study was then repeated in additional two groups of mice

  14. Dictyostelium discoideum Ax2 as an Assay System for Screening of Pharmacological Chaperones for Phenylketonuria Mutations.

    PubMed

    Kim, Yu-Min; Yang, Yun Gyeong; Kim, Hye-Lim; Park, Young Shik

    2015-06-01

    In this study, we developed an assay system for missense mutations in human phenylalanine hydroxylases (hPAHs). To demonstrate the reliability of the system, eight mutant proteins (F39L, K42I, L48S, I65T, R252Q, L255V, S349L, and R408W) were expressed in a mutant strain (pah(-)) of Dictyostelium discoideum Ax2 disrupted in the indigenous gene encoding PAH. The transformed pah- cells grown in FM minimal medium were measured for growth rate and PAH activity to reveal a positive correlation between them. The protein level of hPAH was also determined by western blotting to show the impact of each mutation on protein stability and catalytic activity. The result was highly compatible with the previous ones obtained from other expression systems, suggesting that Dictyostelium is a dependable alternative to other expression systems. Furthermore, we found that both the protein level and activity of S349L and R408W, which were impaired severely in protein stability, were rescued in HL5 nutrient medium. Although the responsible component(s) remains unidentified, this unexpected finding showed an important advantage of our expression system for studying unstable proteins. As an economic and stable cell-based expression system, our development will contribute to mass-screening of pharmacological chaperones for missense PAH mutations as well as to the in-depth characterization of individual mutations.

  15. Phenylketonuria Genetic Screening Simulation

    ERIC Educational Resources Information Center

    Erickson, Patti

    2012-01-01

    After agreeing to host over 200 students on a daylong genetics field trip, the author needed an easy-to-prepare genetics experiment to accompany the DNA-necklace and gel-electrophoresis activities already planned. One of the student's mothers is a pediatric physician at the local hospital, and she suggested exploring genetic-disease screening…

  16. Phenylketonuria Genetic Screening Simulation

    ERIC Educational Resources Information Center

    Erickson, Patti

    2012-01-01

    After agreeing to host over 200 students on a daylong genetics field trip, the author needed an easy-to-prepare genetics experiment to accompany the DNA-necklace and gel-electrophoresis activities already planned. One of the student's mothers is a pediatric physician at the local hospital, and she suggested exploring genetic-disease screening…

  17. ADHD, autism and neuroradiological complications among phenylketonuric children in Upper Egypt.

    PubMed

    Saad, Khaled; Elserogy, Yasser; Abdel Rahman, Ahmed A; Al-Atram, Abdulrahman Abdullah; Mohamad, Ismail L; ElMelegy, Tarek T H; Bjørklund, Geir; El-Houfy, Amira A

    2015-12-01

    The aim of this study is to evaluate the neuropsychological status in a cohort of children with early and continuously treated phenylketonuria in Assiut, Upper Egypt. The study was implemented in seventy-eight phenylketonuria (PKU) children. Only 34 patients met the inclusion criteria. Investigated patients were evaluated according to detailed history, neurological examination, Childhood Autism Rating Scale, full scale Intelligence Quotient, attention deficit hyperactivity disorder, electroencephalography and magnetic resonance imaging (MRI). This study concluded that the prognosis for early diagnosed children with PKU treated from the first weeks of life is generally good. However, they are at increased risk for neurological complications and behavioral problems. So, neonatal screening for PKU is highly recommended in Egypt, for early detection and management. In addition, neuropsychological and MRI assessments in PKU children should be done.

  18. Showing Value in Newborn Screening: Challenges in Quantifying the Effectiveness and Cost-Effectiveness of Early Detection of Phenylketonuria and Cystic Fibrosis

    PubMed Central

    Grosse, Scott D.

    2015-01-01

    Decision makers sometimes request information on the cost savings, cost-effectiveness, or cost-benefit of public health programs. In practice, quantifying the health and economic benefits of population-level screening programs such as newborn screening (NBS) is challenging. It requires that one specify the frequencies of health outcomes and events, such as hospitalizations, for a cohort of children with a given condition under two different scenarios—with or without NBS. Such analyses also assume that everything else, including treatments, is the same between groups. Lack of comparable data for representative screened and unscreened cohorts that are exposed to the same treatments following diagnosis can result in either under- or over-statement of differences. Accordingly, the benefits of early detection may be understated or overstated. This paper illustrates these common problems through a review of past economic evaluations of screening for two historically significant conditions, phenylketonuria and cystic fibrosis. In both examples qualitative judgments about the value of prompt identification and early treatment to an affected child were more influential than specific numerical estimates of lives or costs saved. PMID:26702401

  19. Nutritional Treatment for Inborn Errors of Metabolism: Indications, Regulations, and Availability of Medical Foods and Dietary Supplements Using Phenylketonuria as an Example

    PubMed Central

    Camp, Kathryn M.; Lloyd-Puryear, Michele A.; Huntington, Kathleen L.

    2012-01-01

    Medical foods and dietary supplements are used to treat rare inborn errors of metabolism (IEM) identified through state-based universal newborn screening. These products are regulated under Food and Drug Administration (FDA) food and dietary supplement statutes. The lack of harmony in terminology used to refer to medical foods and dietary supplements and the misuse of words that imply that FDA regulates these products as drugs have led to confusion. These products are expensive and, although they are used for medical treatment of IEM, third-party payer coverage of these products is inconsistent across the United States. Clinicians and families report termination of coverage in late adolescence, failure to cover treatment during pregnancy, coverage for select conditions only, or no coverage. We describe the indications for specific nutritional treatment products for IEM and their regulation, availability, and categorization. We conclude with a discussion of the problems that have contributed to the paradox of identifying individuals with IEM through newborn screening but not guaranteeing that they receive optimal treatment. Throughout the paper, we use the nutritional treatment of phenylketonuria as an example of IEM treatment. PMID:22854513

  20. Using simple molecular orbital calculations to predict disease: fast DFT methods applied to enzymes implicated in PKU, Parkinson's disease and Obsessive Compulsive Disorder

    NASA Astrophysics Data System (ADS)

    Hofto, Laura; Hofto, Meghan; Cross, Jessica; Cafiero, Mauricio

    2007-09-01

    Many diseases can be traced to point mutations in the DNA coding for specific enzymes. These point mutations result in the change of one amino acid residue in the enzyme. We have developed a model using simple molecular orbital calculations which can be used to quantitatively determine the change in interaction between the enzyme's active site and necessary ligands upon mutation. We have applied this model to three hydroxylase proteins: phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase, and we have obtained excellent correlation between our results and observed disease symptoms. Furthermore, we are able to use this agreement as a baseline to screen other mutations which may also cause onset of disease symptoms. Our focus is on systems where the binding is due largely to dispersion, which is much more difficult to model inexpensively than pure electrostatic interactions. Our calculations are run in parallel on a sixteen processor cluster of 64-bit Athlon processors.

  1. Monkey Retardate Learning Analysis

    ERIC Educational Resources Information Center

    Chamove, A. S.; Molinaro, T. J.

    1978-01-01

    Seven rhesus monkeys reared on diets high in phenylalanine to induce phenylketonuria (PKU--a metabolic disorder associated with mental retardation if untreated) were compared with normal, pair-fed, and younger controls; frontal brain-lesioned monkeys; and those raised on high-tryptophan diets in three object discrimination tasks. (Author)

  2. SOME FACTS AND FIGURES ABOUT CHILDREN AND YOUTH.

    ERIC Educational Resources Information Center

    Children's Bureau (DHEW), Washington, DC.

    IN QUESTION AND ANSWER FORM, THE PAMPHLET PRESENTS STATISTICAL DATA ON CHILDREN AND YOUTH PRIMARILY IN THE UNITED STATES. INFORMATION CONCERNS POPULATION, RESIDENCE, MOBILITY, POVERTY, WORKING MOTHERS, MARRIAGES, DIVORCES, BIRTHS, LIFE EXPECTANCY, MORTALITY, ILLNESS, HANDICAPS, HOSPITALIZATION, ADOPTIONS, PHENYLKETONURIA (PKU) LAWS, CHILD ABUSE…

  3. Current Status of Newborn Screening: Decision-Making about the Conditions to Include in Screening Programs

    ERIC Educational Resources Information Center

    Watson, Michael S.

    2006-01-01

    Newborn screening is considered a highly successful public health program that has resulted in the reduction of mortality, mental retardation, and other serious disabilities in thousands of children since the introduction of screening for phenylketonuria (PKU) in the 1960s. Programs are based in state public health departments such that each state…

  4. Current Status of Newborn Screening: Decision-Making about the Conditions to Include in Screening Programs

    ERIC Educational Resources Information Center

    Watson, Michael S.

    2006-01-01

    Newborn screening is considered a highly successful public health program that has resulted in the reduction of mortality, mental retardation, and other serious disabilities in thousands of children since the introduction of screening for phenylketonuria (PKU) in the 1960s. Programs are based in state public health departments such that each state…

  5. SOME FACTS AND FIGURES ABOUT CHILDREN AND YOUTH.

    ERIC Educational Resources Information Center

    Children's Bureau (DHEW), Washington, DC.

    IN QUESTION AND ANSWER FORM, THE PAMPHLET PRESENTS STATISTICAL DATA ON CHILDREN AND YOUTH PRIMARILY IN THE UNITED STATES. INFORMATION CONCERNS POPULATION, RESIDENCE, MOBILITY, POVERTY, WORKING MOTHERS, MARRIAGES, DIVORCES, BIRTHS, LIFE EXPECTANCY, MORTALITY, ILLNESS, HANDICAPS, HOSPITALIZATION, ADOPTIONS, PHENYLKETONURIA (PKU) LAWS, CHILD ABUSE…

  6. Monkey Retardate Learning Analysis

    ERIC Educational Resources Information Center

    Chamove, A. S.; Molinaro, T. J.

    1978-01-01

    Seven rhesus monkeys reared on diets high in phenylalanine to induce phenylketonuria (PKU--a metabolic disorder associated with mental retardation if untreated) were compared with normal, pair-fed, and younger controls; frontal brain-lesioned monkeys; and those raised on high-tryptophan diets in three object discrimination tasks. (Author)

  7. Environmental factors and disturbances of brain development.

    PubMed

    Gressens, P; Mesples, B; Sahir, N; Marret, S; Sola, A

    2001-04-01

    Foetal and neonatal brain is under the influence of environmental factors from maternal and extra-maternal origin. Based on the available data, these environmental factors can be classified into three arbitrary groups: (i) factors and maternal status with a demonstrated deleterious effect on the foetal brain (i.e. ethanol, cocaine, some drugs including anticonvulsants, some viral infections, maternal diabetes, untreated maternal phenylketonuria); (ii) factors highly suspected to interfere with foetal brain development (i.e. lead and other heavy metals, some drugs like benzodiazepines, nicotine); (iii) factors which have been shown to be safe for the developing brain in the available studies (i.e. low to moderate doses of caffeine, methadone). However, most of these studies do not address the potential risk of environmental factors on minimal to moderate cognitive and behavioural disturbances. Finally, the impact of the neonatal environment on brain development in very pre-term infants is probably underestimated. Copyright 2000 Harcourt Publishers Ltd.

  8. Computational study of missense mutations in phenylalanine hydroxylase.

    PubMed

    Réblová, Kamila; Kulhánek, Petr; Fajkusová, Lenka

    2015-04-01

    Hyperphenylalaninemia (HPA) is one of the most common metabolic disorders. HPA, which is transmitted by an autosomal recessive mode of inheritance, is caused by mutations of the phenylalanine hydroxylase gene. Most mutations are missense and lead to reduced protein stability and/or impaired catalytic function. The impact of such mutations varies, ranging from classical phenylketonuria (PKU), mild PKU, to non-PKU HPA phenotypes. Despite the fact that HPA is a monogenic disease, clinical data show that one PKU genotype can be associated with more in vivo phenotypes, which indicates the role of other (still unknown) factors. To better understand the phenotype-genotype relationships, we analyzed computationally the impact of missense mutations in homozygotes stored in the BIOPKU database. A total of 34 selected homozygous genotypes was divided into two main groups according to their phenotypes: (A) genotypes leading to non-PKU HPA or combined phenotype non-PKU HPA/mild PKU and (B) genotypes leading to classical PKU, mild PKU or combined phenotype mild PKU/classical PKU. Combining in silico analysis and molecular dynamics simulations (in total 3 μs) we described the structural impact of the mutations, which allowed us to separate 32 out of 34 mutations between groups A and B. Testing the simulation conditions revealed that the outcome of mutant simulations can be modulated by the ionic strength. We also employed programs SNPs3D, Polyphen-2, and SIFT but based on the predictions performed we were not able to discriminate mutations with mild and severe PKU phenotypes.

  9. Essentials of PKU for Young Adults with PKU and Their Significant Others

    MedlinePlus

    ... 1) Phenylalanine is only one of the many amino acids which are joined together to form proteins. Normally, ... eats foods containing protein, their body uses the amino acids from that protein for growth and repair of ...

  10. Determination of Phenylalanine and Tyrosine by High Performance Liquid Chromatography-Tandem Mass Spectrometry.

    PubMed

    Peat, Judy; Garg, Uttam

    2016-01-01

    Hyperphenylalaninemia/phenylketonuria (PKU) is one of the most common inborn errors of amino acid metabolism affecting about 1:15,000 infants in the United States. PKU is an autosomal recessive disorder that if untreated results in mental retardation. The most common cause of PKU is deficiency of the enzyme phenylalanine hydroxylase that converts phenylalanine to tyrosine. Tyrosine deficiency results in impaired synthesis of catecholamines and thyroxine. Less commonly, it can result from defects in the synthesis or regeneration of tetrahydrobiopterin (BH4), an essential cofactor for the enzyme phenylalanine hydroxylase. Increased phenylalanine and decreased tyrosine in blood are used in the diagnosis and follow-up of patients with PKU. LC/MS/MS method is described for the quantification of phenylalanine and tyrosine.

  11. Screening Out Controversy: Human Genetics, Emerging Techniques of Diagnosis, and the Origins of the Social Issues Committee of the American Society of Human Genetics, 1964-1973.

    PubMed

    Mitchell, M X

    2017-05-01

    In the years following World War II, and increasingly during the 1960s and 1970s, professional scientific societies developed internal sub-committees to address the social implications of their scientific expertise (Moore, Disrupting Science: Social Movements, American Scientists, and the Politics of the Military, 1945-1975. Princeton: Princeton University Press, 2008). This article explores the early years of one such committee, the American Society of Human Genetics' "Social Issues Committee," founded in 1967. Although the committee's name might suggest it was founded to increase the ASHG's public and policy engagement, exploration of the committee's early years reveals a more complicated reality. Affronted by legislators' recent unwillingness to seek the expert advice of human geneticists before adopting widespread neonatal screening programs for phenylketonuria (PKU), and feeling pressed to establish their relevance in an increasingly resource-scarce funding environment, committee members sought to increase the discipline's expert authority. Painfully aware of controversy over abortion rights and haunted by the taint of the discipline's eugenic past, however, the committee proceeded with great caution. Seeking to harness interest in and assert professional control over emerging techniques of genetic diagnosis, the committee strove to protect the society's image by relegating ethical and policy questions about their use to the individual consciences of member scientists. It was not until 1973, after the committee's modest success in organizing support for a retrospective public health study of PKU screening and following the legalization of abortion on demand, that the committee decided to take a more publicly engaged stance.

  12. Cultural aspects in the management of inborn errors of metabolism.

    PubMed

    Stockler, Sylvia; Moeslinger, Dorothea; Herle, Marion; Wimmer, Banu; Ipsiroglu, Osman S

    2012-11-01

    European Health Care Systems have not yet accommodated both previous and current migration waves. Children from immigrant families, especially children with chronic conditions, are particularly affected from the shortcomings in medical care. One condition, phenylketonuria (PKU), is an inborn error of metabolism (IEM) which results in intellectual disability unless treated with a lifelong phenylalanine (Phe) restricted diet. In our PKU clinic, patients from families who previously had emmigrated from the geographic area of Turkey to Austria, exhibited worse blood Phe control and cognitive development than comparable patients from native Austrian families. Using structured and semi-structured interviews, questionnaires, and illness narratives, we identified language, psychosocial, economic, educational and cultural barriers as factors influencing adherence to treatment. Our findings led us to conclude that access to interpreter services, exploration of the socio-cultural background and of family ecology, as well as bi-directional communication and medical decision making according to the "best interest of the child" principle, may improve outcomes in patients requiring complex treatment and care.

  13. International cooperation in neonatal screening: technical training course for newborn and infant screening.

    PubMed

    Fukushi, M; Hanai, J; Yamaguchi, A; Mikami, A; Honma, K; Nomura, Y; Arai, O; Tagami, Y; Oda, H; Fujita, K

    1999-01-01

    We report the outline and results of our experience with a group training course of neonatal screening for health care professionals in developing countries. Sapporo City Institute of Public Health (SCIPH) has been offered a training course on neonatal screening once a year since 1991 under the Technical Training Program of the Japan International Cooperation Agency (JICA). The aims of this training course are to enhance the participants' technical knowledge and skills, and also to deepen their understanding of the principle of neonatal screening as well as the relevant diseases. Lectures and laboratory practice on phenylketonuria (PKU), congenital hypothyroidism (CH), congenital adrenal hyperplasia (CAH) and neuroblastoma are included in the 3-month program. After the completion of the training, participants are expected to play a major role in establishing and expanding neonatal screening system in each of their countries. We have received a total of 67 participants from 25 countries until March 1998: 58 pediatricians; 2 gynecologists; 6 biochemists; 1 administrative officer. After they returned to their countries, 11 engaged in neonatal screening and started PKU and CH screening in their institute, city or province in Argentina, Brazil, Mexico, Peru and Thailand. We believe that these results fulfilled our objectives. Also, for follow-up, SCIPH has been giving information and consultation to the participants on requests. This international cooperation network could also benefit our present network of the International Society Screening in the future.

  14. [Risk-sharing scheme in Israel--Kuvan as an allegory].

    PubMed

    Abadi-Korek, Ifat; Shemer, Joshua

    2012-06-01

    Healthcare systems worldwide are dealing with the uncertainty characterizing new and expensive health technoLogies, particularly aspects involving drug effectiveness and the extent and doses required for utilization. Reducing this uncertainty can be achieved mainly by using either coverage with evidence development methods or risk-sharing schemes (RSS). In 2011, the first phenylketonuria (PKU) risk-sharing scheme was set up in Israel, through the public funding health services updating process. This was done in order to ensure that people with PKU could access PKU sole treatment--sapropterin dihydrochloride, Kuvan. The apparent effectiveness of the treatment, on one hand, and the uncertainty regarding the number of patients and average treatment dosage, on the other hand, dictated the RRS. This scheme determined a ceiling number of tablets to be funded by the insurer, above this ceiling the manufacturer would finance Kuvan. Furthermore, it was agreed that after 3 years Kuvan would be brought to the public committee for updating reimbursement decisions. It is inevitable that risk sharing and conditional coverage agreements will become a common practice in the reimbursement process in the future. This will allow competent authorities and pharmaceutical companies to build clinical experience and other required data with medicines which might normally not be eLigible for reimbursement. Before it becomes the common practice in Israel, the RSS for Kuvan, process and outcomes, should be monitored and analyzed by the Ministry of Health, to ensure patients access to treatment, the effective collection of the research data and the effective interaction between Israel's four health funds and the manufacturer.

  15. Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene.

    PubMed

    Bercovich, Dani; Elimelech, Arava; Zlotogora, Joel; Korem, Sigal; Yardeni, Tal; Gal, Nurit; Goldstein, Nurit; Vilensky, Bela; Segev, Roni; Avraham, Smadar; Loewenthal, Ron; Schwartz, Gerard; Anikster, Yair

    2008-01-01

    The aims of our research were to define the genotype-phenotype correlations of mutations in the phenylalanine hydroxylase (PAH) gene that cause phenylketonuria (PKU) among the Israeli population. The mutation spectrum of the PAH gene in PKU patients in Israel is described, along with a discussion on genotype-phenotype correlations. By using polymerase chain reaction/denaturing high-performance liquid chromatography (PCR/dHPLC) and DNA sequencing, we screened all exons of the PAH gene in 180 unrelated patients with four different PKU phenotypes [classic PKU, moderate PKU, mild PKU, and mild hyperphenylalaninemia (MHP)]. In 63.2% of patient genotypes, the metabolic phenotype could be predicted, though evidence is also found for both phenotypic inconsistencies among subjects with more than one type of mutation in the PAH gene. Data analysis revealed that about 25% of patients could participate in the future in (6R)-L: -erythro-5, 6, 7, 8-tetrahydrobiopterin (BH4) treatment trials according to their mutation genotypes. This study enables us to construct a national database in Israel that will serve as a valuable tool for genetic counseling and a prognostic evaluation of future cases of PKU.

  16. Differential Effects of Low-Phenylalanine Protein Sources on Brain Neurotransmitters and Behavior in C57Bl/6-Pahenu2 Mice

    PubMed Central

    Sawin, Emily A.; Murali, Sangita G.; Ney, Denise M.

    2014-01-01

    Phenylketonuria (PKU) is an inborn error of metabolism caused by a deficiency of the enzyme phenylalanine hydroxylase, which metabolizes phenylalanine (phe) to tyrosine. A low-phe diet plus amino acid (AA) formula is necessary to prevent cognitive impairment; glycomacropeptide (GMP) contains minimal phe and provides a palatable alternative to the AA formula. Our objective was to assess neurotransmitter concentrations in brain and the behavioral phenotype of PKU mice (Pahenu2 on the C57Bl/6 background) and how this is affected by low-phe protein sources. Wild type (WT) and PKU mice, both male and female, were fed high-phe casein, low-phe AA, or low-phe GMP diets between 3–18 weeks of age. Behavioral phenotype was assessed using the open field and marble burying tests, and brain neurotransmitter concentration measured using HPLC with electrochemical detection system. Data were analyzed by 3-way ANOVA with genotype, sex, and diet as the main treatment effects. Brain mass and the concentrations of catecholamines and serotonin were reduced in PKU mice compared to WT mice; the low-phe AA and GMP diets improved these parameters in PKU mice. Relative brain mass was increased in female PKU mice fed the GMP diet compared to the AA diet. PKU mice exhibited hyperactivity and impaired vertical exploration compared to their WT littermates during the open field test. Regardless of genotype or diet, female mice demonstrated increased vertical activity time and increased total ambulatory and horizontal activity counts compared with male mice. PKU mice fed the high-phe casein diet buried significantly fewer marbles than WT control mice fed casein; this was normalized in PKU mice fed the low-phe AA and GMP diets. In summary, C57Bl/6-Pahenu2 mice showed an impaired behavioral phenotype and reduced brain neurotransmitter concentrations that were improved by the low-phe AA or GMP diets. These data support lifelong adherence to a low-phe diet for PKU. PMID:24560888

  17. Cartoons vs. realistic illustration: picture preferences of adolescent patients.

    PubMed

    Dirr, K L; Katz, A A

    1989-01-01

    Illustrations are an important element in patient education materials because they engage the interest of the audience. However, little research has been conducted to determine the style of illustration that most effectively engages a patient population. This study tested the picture preferences of 39 adolescents with phenylketonuria (PKU). A survey instrument asked them to choose between cartoons and realistic illustrations. A significant number preferred realistic illustrations to cartoons.

  18. Newborn Screening in Slovenia

    PubMed Central

    ŠMON, Andraž; GROŠELJ, Urh; ŽERJAV TANŠEK, Mojca; BIČEK, Ajda; OBLAK, Adrijana; ZUPANČIČ, Mirjana; KRŽIŠNIK, Ciril; REPIČ LAMPR ET, Barbka; MURKO, Simona; HOJKER, Sergej; BATTELINO, Tadej

    2015-01-01

    Introduction Newborn screening in whole Slovenia started in 1979 with screening for phenylketonuria (PKU). Congenital hypothyroidism (CH) was added into the programme in 1981. The aim of this study was to analyse the data of neonatal screening in Slovenia from 1993 to 2012 for PKU, and from 1991 to 2012 for CH. Methods Blood samples were collected from the heels of newborns between the third and the fifth day after birth. Fluorometric method was used for screening for PKU, CH screening was done by dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA). Results From 1993 to 2012, from 385,831 newborns 57 were identified with PKU. 184 newborns out of 427,396 screened from 1991 to 2012, were confirmed for CH. Incidences of PKU and CH in the periods stated are 1:6769 and 1:2323, respectively. Conclusions Successful implementation of newborn screening for PKU and CH has helped in preventing serious disabilities of the affected children. Adding screening for new metabolic diseases in the future would be beneficial. PMID:27646913

  19. Phenylalanine hydroxylase misfolding and pharmacological chaperones.

    PubMed

    Underhaug, Jarl; Aubi, Oscar; Martinez, Aurora

    2012-01-01

    Phenylketonuria (PKU) is a loss-of-function inborn error of metabolism. As many other inherited diseases the main pathologic mechanism in PKU is an enhanced tendency of the mutant phenylalanine hydroxylase (PAH) to misfold and undergo ubiquitin-dependent degradation. Recent alternative approaches with therapeutic potential for PKU aim at correcting the PAH misfolding, and in this respect pharmacological chaperones are the focus of increasing interest. These compounds, which often resemble the natural ligands and show mild competitive inhibition, can rescue the misfolded proteins by stimulating their renaturation in vivo. For PKU, a few studies have proven the stabilization of PKU-mutants in vitro, in cells, and in mice by pharmacological chaperones, which have been found either by using the tetrahydrobiopterin (BH(4)) cofactor as query structure for shape-focused virtual screening or by high-throughput screening of small compound libraries. Both approaches have revealed a number of compounds, most of which bind at the iron-binding site, competitively with respect to BH(4). Furthermore, PAH shares a number of ligands, such as BH(4), amino acid substrates and inhibitors, with the other aromatic amino acid hydroxylases: the neuronal/neuroendocrine enzymes tyrosine hydroxylase (TH) and the tryptophan hydroxylases (TPHs). Recent results indicate that the PAH-targeted pharmacological chaperones should also be tested on TH and the TPHs, and eventually be derivatized to avoid unwanted interactions with these other enzymes. After derivatization and validation in animal models, the PAH-chaperoning compounds represent novel possibilities in the treatment of PKU.

  20. Urinary biomarkers of oxidative stress and plasmatic inflammatory profile in phenylketonuric treated patients.

    PubMed

    Deon, Marion; Sitta, Angela; Faverzani, Jessica L; Guerreiro, Gillian B; Donida, Bruna; Marchetti, Desirèe P; Mescka, Caroline P; Ribas, Graziela S; Coitinho, Adriana S; Wajner, Moacir; Vargas, Carmen R

    2015-12-01

    Oxidative stress has been proposed as an important pathophysiologic feature of various inborn errors of metabolism, including phenylketonuria (PKU). Considering that there are few studies relating oxidative stress and inflammation directly in PKU disease, the aim of this study was to evaluate and correlate oxidative damage to biomolecules, antioxidant defenses, pro-inflammatory cytokines, phenylalanine (Phe) and its metabolites (phenyllactic acid--PLA and phenylacetic acid--PAA) levels in urine and plasma from patients with PKU under dietary treatment. We observed a marked increase of isoprostanes, which is a lipid peroxidation biomarker, in urine from these treated patients. Next, we demonstrated that protein oxidative damage, measured by di-tyrosine formation, was significantly increased in urine from PKU treated patients and that decreased urinary antioxidant capacity was also observed. Our findings concerning to the inflammatory cytokines interleukin-6 and interleukin-1β, both significantly increased in these patients, provide evidence that the pro-inflammatory state occurs. Besides, interleukin-1β was positively correlated with isoprostanes. We observed a negative correlation between interleukin-6 and interleukin-10, an anti-inflammatory cytokine. Di-tyrosine was positively correlated with Phe, which indicates oxidative damage to proteins, as well as with PAA. These findings may suggest that the protein damage may be induced by Phe and its metabolite PAA in PKU. Our results indicate that pro-oxidant and pro-inflammatory states occur and are, in part, correlated and protein oxidation seems to be induced by Phe and PPA in PKU patients.

  1. Tuning for the first 9-cell TESLA cavity of PKU

    NASA Astrophysics Data System (ADS)

    Yang, Liu; He, Fei-Si; Xu, Wen-Can; Zhu, Feng; Lu, Xiang-Yang; Zhao, Kui

    2010-04-01

    A method based on circuit model is used to tune the first home-made 9-cell TESLA type superconducting niobium cavity at Peking University. After tuning, a flat field profile with a final π-mode frequency within 3 kHz of target frequency is achieved. The field flatness is measured by a bead-pull method, and the relative electric field is calculated from the frequency shift perturbed by the bead stepping along the axis of the cavity.

  2. [The development of molecular human genetics and its significance for perspectives of modern medicine].

    PubMed

    Coutelle, C; Speer, A; Grade, K; Rosenthal, A; Hunger, H D

    1989-01-01

    The introduction of molecular human genetics has become a paradigma for the application of genetic engineering in medicine. The main principles of this technology are the isolation of molecular probes, their application in hybridization reactions, specific gene-amplification by the polymerase chain reaction, and DNA sequencing reactions. These methods are used for the analysis of monogenic diseases by linkage studies and the elucidation of the molecular defect causing these conditions, respectively. They are also the basis for genomic diagnosis of monogenic diseases, introduced into the health care system of the GDR by a national project on Duchenne/Becker muscular dystrophy, Cystic Fibrosis and Phenylketonuria. The rapid development of basic research on the molecular analysis of the human genome and genomic diagnosis indicates, that human molecular genetics is becoming a decisive basic discipline of modern medicine.

  3. Development

    ERIC Educational Resources Information Center

    Furtado, Celso

    1977-01-01

    Examines the interdisciplinary nature of theories of development. Topics discussed include views of history, instrumental rationality, the role of technology in capitalist society, and a synthetic view of the development/underdevelopment process. For journal availability, see SO 506 201. (Author/DB)

  4. [Lipids composition diet in phenylketonuric children with early diagnosis].

    PubMed

    Cornejo, Verónica; Concha, Miluska; Cabello, Juan Francisco; Raimann, Erna

    2005-12-01

    Phenylketonuria (PKU) is a genetic disorder caused by a partial or complete mutation of the enzyme phenylalanine hydroxylase (PHA), fact that produces high levels of phenylalanine in blood resulting in mental retardation if not diagnosed during the neonatal period. Treatment consists of a phenylalanine (Phe) restricted diet. Several studies have shown that due to restriction of animal protein, this diet is deficient in fatty acids such as alfalinolenic acid (ALA) and provides high levels of linoleic acid (LA). The objective of this study was to determine the lipid composition of the diet consumed by children with early-diagnosed PKU. Lipid composition of the Phenylalanine restricted diet consumed by 29 children with PKU and in follow-up at INTA, University of Chile, were analyzed. Children were paired by sex and age with a control group. A twenty-four hour dietary recall was performed for 3 consecutive days and total fatty acid intake, including saturated, monounsaturated, polyunsaturated, LA and ALA, were calculated. In the restricted diet of children with PKU, 31.8% of total calories are from fat, 13% of which are LA and 0.2% ALA, showing significant differences as compared to the control group. The ratio of saturated:monounsaturated:polyunsaturated fatty acids was 1:1.7:3.9 and the ratio of LA:ALA was ten-fold higher than the recommended ratio of 115:1. It is concluded that the Phenyalanine restricted diet of Chilean children with PKU is high in LA and low in ALA.

  5. Development

    ERIC Educational Resources Information Center

    Childress, Dana C.; Raver, Sharon A.; Michalek, Anne M. P.; Wilson, Corinne L.

    2013-01-01

    All eligible infants and toddlers who receive early intervention services under Part C of Individuals with Disabilities Education Act are entitled to service coordination. To examine the effectiveness of one state's service coordination training and its impact on knowledge and skill development, a pretest--posttest design with follow-up survey was…

  6. Development

    ERIC Educational Resources Information Center

    Childress, Dana C.; Raver, Sharon A.; Michalek, Anne M. P.; Wilson, Corinne L.

    2013-01-01

    All eligible infants and toddlers who receive early intervention services under Part C of Individuals with Disabilities Education Act are entitled to service coordination. To examine the effectiveness of one state's service coordination training and its impact on knowledge and skill development, a pretest--posttest design with follow-up survey was…

  7. Nano-Calorimetry based point of care biosensor for metabolic disease management.

    PubMed

    Kazura, Evan; Lubbers, Brad R; Dawson, Elliott; Phillips, John A; Baudenbacher, Franz

    2017-09-01

    Point of care (POC) diagnostics represents one of the fastest growing health care technology segments. Developments in microfabrication have led to the development of highly-sensitive nanocalorimeters ideal for directly measuring heat generated in POC biosensors. Here we present a novel nano-calorimeter-based biosensor design with differential sensing to eliminate common mode noise and capillary microfluidic channels for sample delivery to the thermoelectric sensor. The calorimeter has a resolution of 1.4 ± 0.2 nJ/(Hz)(1/2) utilizing a 27 junction bismuth/titanium thermopile, with a total Seebeck coefficient of 2160 μV/K. Sample is wicked to the calorimeter through a capillary channel making it suitable for monitoring blood obtained through a finger prick (<1 μL sample required). We demonstrate device performance in a model assay using catalase, achieving a threshold for hydrogen peroxide quantification of 50 μM. The potential for our device as a POC blood test for metabolic diseases is shown through the quantification of phenylalanine (Phe) in serum, an unmet necessary service in the management of Phenylketonuria (PKU). Pegylated phenylalanine ammonia-lyase (PEG-PAL) was utilized to react with Phe, but reliable detection was limited to <5 mM due to low enzymatic activity. The POC biosensor concept can be multiplexed and adapted to a large number of metabolic diseases utilizing different immobilized enzymes.

  8. Spectrofluorimetric determination of phenylalanine based on fluorescence enhancement of europium ion immobilized with sol-gel method

    NASA Astrophysics Data System (ADS)

    Zhang, Kun; Yan, Hong-Tao; Zhou, Tie

    2011-12-01

    The analysis of phenylalanine (Phe) in serum is widely performed for the screening of newborn phenylketonuria (PKU). In this work, a novel spectrofluorimetric method for the determination of Phe was developed based on the fluorescence enhancement of Ruhemann's purple, the reaction product between Phe and ninhydrin, upon coordination with Eu 3+. A filter paper disc containing immobilized reactants (ninhydrin and Eu 3+) was fabricated by sol-gel method. The experimental parameters affecting the determination of Phe, such as the concentrations of immobilized reagents, the pH value, the reaction time and temperature were optimized. Under optimum conditions, the fluorescence intensity of Phe-ninhydrin-Eu 3+ system was linearly proportional to the concentration of Phe in the range from 5 × 10 -5 to 2 × 10 -3 mol L -1, and the limit of detection was found to be 5.2 × 10 -6 mol L -1. The relative standard deviation was 2.6% for ten replicate measurements of 1.5 × 10 -4 mol L -1 of Phe. The method has merits of sensitivity, simplicity and low cost, and has been applied to the determination of Phe in artificial serum.

  9. A framework for assessing outcomes from newborn screening: on the road to measuring its promise

    PubMed Central

    Hinton, Cynthia F.; Homer, Charles J.; Thompson, Alexis A.; Williams, Andrea; Hassell, Kathryn L.; Feuchtbaum, Lisa; Berry, Susan A.; Comeau, Anne Marie; Therrell, Bradford L.; Brower, Amy; Harris, Katharine B.; Brown, Christine; Monaco, Jana; Ostrander, Robert J.; Zuckerman, Alan E.; Kaye, Celia; Dougherty, Denise; Greene, Carol; Green, Nancy S.

    2016-01-01

    Newborn screening (NBS) is intended to identify congenital conditions prior to the onset of symptoms in order to provide early intervention that leads to improved outcomes. NBS is a public health success, providing reduction in mortality and improved developmental outcomes for screened conditions.. However, it is less clear to what extent newborn screening achieves the long-term goals relating to improved health, growth, development and function. We propose a framework for assessing outcomes for the health and well-being of children identified through NBS programs. The framework proposed here, and this manuscript, were approved for publication by the Secretary of Health and Human Services’ Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC). This framework can be applied to each screened condition within the Recommended Uniform Screening Panel (RUSP), recognizing that the data elements and measures will vary by condition. As an example, we applied the framework to sickle cell disease and phenylketonuria (PKU), two diverse conditions with different outcome measures and potential sources of data. Widespread and consistent application of this framework across state NBS and child health systems is envisioned as useful to standardize approaches to assessment of outcomes and for continuous improvement of the NBS and child health systems. PMID:27268406

  10. The development and organization of newborn screening programs in Turkey.

    PubMed

    Tezel, Başak; Dilli, Dilek; Bolat, Hilal; Sahman, Hatice; Ozbaş, Sema; Acıcan, Deniz; Ertek, Mustafa; Köse, Mehmet Rıfat; Dilmen, Uğur

    2014-01-01

    Newborn screening tests have been designed to identify infants with severe disorders that are relatively prevalent and treatable or controllable. Comparing to other countries, the incidence of these diseases are very high in Turkey where the rate of consanguineous marriage is high. In this article, it is aimed to evaluate the development and organization of newborn screening programs in Turkey which include phenylketonuria, congenital hypothyroidism and biotinidase deficiency screenings. The point reached today, limitations of the program, expectations and projects for the future are discussed. Today, the point reached in screening programs of the country is appreciable. While the screening rate of the live born babies was 4,7% in 1987, this rate reached to 95% by 2008. Predicted target for newborn screening program at the strategic plan of Ministry of Health for 2010-2014 was to enhance this rate above 95% by the end of 2012. It seems that the envisaged goal has been reached. National newborn screening program appears to be conducted successfully and extensively as a result of political determination and performance of health care workers who are in charge of this program. Nevertheless, limited numbers of the nutrition and metabolism clinics and specialists on these branches have caused some access difficulties, waste of time, and financial loss. Therefore, special planning to improve quality and the number of the clinics would be useful. © 2013 Wiley Periodicals, Inc.

  11. Unresponsiveness to tetrahydrobiopterin of phenylalanine hydroxylase deficiency.

    PubMed

    Ponzone, Alberto; Porta, Francesco; Mussa, Alessandro; Alluto, Alessandra; Ferraris, Silvio; Spada, Marco

    2010-05-01

    Conflicting results have been reported concerning the efficacy of tetrahydrobiopterin (BH4), the cofactor of phenylalanine hydroxylase, for reducing phenylalanine (Phe) concentration in phenylketonuria (PKU). We aimed to test quantitatively the effects of BH4 in PKU patients. Seven fully characterized patients were selected among a population of 130 PKU subjects as harboring PKU mutations predicted as BH4 responsive and previously considered responsive to a cofactor challenge. They received a simple Phe (100 mg/kg) and 2 combined Phe (100 mg/kg) and BH4 (20 mg/kg) oral loading tests. Cofactor was administered either before or after the amino acid. The concentrations of Phe, tyrosine (Tyr), and biopterin were measured over 24 hours after loading. The comparative analysis of the loading tests showed that in all patients plasma Phe concentrations peaked within 3 hours, and fell within 24 hours by about 50% in benign, 20% in mild, and 15% in severe phenylalanine hydroxylase deficiency regardless of BH4 administration. A consistent or moderate increase of plasma Tyr, again independent of the cofactor challenge, was observed only in the less severe forms of PAH deficiency. Mean blood biopterin concentration increased 6 times after simple Phe and 34 to 39 times after combined loading tests. The administration of BH4 does not alter Phe and Tyr metabolism in PKU patients. The clearance of plasma Phe after oral loading and, as well as Tyr production, is not related to cofactor challenge but to patient's phenotype. The assessment of BH4 responsiveness by the methods so far used is not reliable, and the occurrence of BH4-responsive forms of PKU still has to be definitely proven.

  12. Phenylalanine hydroxylase deficiency caused by a single base substitution in an exon of the human phenylalanine hydroxylase gene

    SciTech Connect

    Lichter-Konecki, U.; Konecki, D.S.; DiLella, A.G.; Brayton, K.; Marvit, J.; Hahn, T.M.; Trefz, E.K.; Woo, S.L.C.

    1988-04-19

    A novel restriction fragment length polymorphism in the phenylalanine hydroxylase (PAH) locus generated by the restriction endonuclease MspI was observed in a German phenylketonuria (PKU) patient. Molecular cloning and DNA sequence analyses revealed that the MspI polymorphism was created by a T to C transition in exon 9 of the human PAH gene, which also resulted in the conversion of a leucine codon to proline codon. The effect of the amino acid substitution was investigated by creating a corresponding mutation in a full-length human PAD cDNA by site-directed mutagenesis followed by expression analysis in cultured mammalian cells. Results demonstrate that the mutation in the gene causes the synthesis of an unstable protein in the cell corresponding to a CRM/sup -/ phenotype. Together with the other mutations recently reported in the PAH gene,the data support previous biochemical and clinical observations that PKU is a heterogeneous disorder at the gene level.

  13. Urinary excretion of N-acetyl amino acids in patients with some inborn errors of amino acid metabolism.

    PubMed

    Jellum, E; Horn, L; Thoresen, O; Kvittingen, E A; Stokke, O

    1986-01-01

    Urinary organic acid profiles of patients with Maple Syrup Urine Disease (MSUD), hereditary tyrosinemia and phenylketonuria (PKU) have been studied by means of capillary GC-MS-computer technique. In addition to the characteristic metabolites of these disorders, increased amounts of N-acetylleucine, N-acetylisoleucine and N-acetylvaline were found in MSUD-urine. Increased excretion of N-acetylphenylalanine occurred in PKU, and in tyrosinemia both the latter compound and increased N-acetyltyrosine excretion were observed. These results together with literature reports of similar studies on patients with other aminoacidopathies may indicate that most disorders which result in accumulation of one or more specific amino acids, will convert a small fraction of them into their corresponding N-acetyl derivative.

  14. An olfactory discrimination procedure for mice.

    PubMed Central

    Mihalick, S M; Langlois, J C; Krienke, J D; Dube, W V

    2000-01-01

    This paper describes an olfactory discrimination procedure for mice that is inexpensively implemented and leads to rapid discrimination learning. Mice were first trained to dig in small containers of sand to retrieve bits of buried chocolate. For discrimination training, two containers were presented simultaneously for eight trials per session. One container held sand mixed with cinnamon, and the other held sand mixed with nutmeg. Both containers were baited with chocolate buried in the sand. One odor was designated S+, and mice were allowed to dig and retrieve the chocolate from this container. The other odor was S-, and both containers were removed immediately if subjects began to dig in an S- container. After meeting a two-session acquisition criterion, subjects were given a series of discrimination reversals. In Experiment 1, 12 Swiss-Webster mice (6 male and 6 female) acquired the olfactory discrimination in three to five sessions and completed 3 to 10 successive discrimination reversals within a 50-session testing limit. In Experiment 2, subjects were 14 Pah(enu2) mice, the mouse mutant for phenylketonuria; 7 were homozygotes in which the disorder was expressed (PKU), and 7 were heterozygotes with normal metabolism (non-PKU). Thirteen mice completed pretraining in four to seven sessions, acquisition required 3 to 12 sessions, and all mice completed at least three reversals. Learning rates were similar in PKU and non-PKU mice. We discuss issues related to implementation and several potentially useful procedural variations. PMID:10866354

  15. DNA damage induced by phenylalanine and its analogue p-chlorophenylalanine in blood and brain of rats subjected to a model of hyperphenylalaninemia.

    PubMed

    Simon, Kellen R; Dos Santos, Rosane M; Scaini, Giselli; Leffa, Daniela D; Damiani, Adriani P; Furlanetto, Camila B; Machado, Jéssica L; Cararo, José H; Macan, Tamires P; Streck, Emilio L; Ferreira, Gustavo C; Andrade, Vanessa M; Schuck, Patrícia F

    2013-10-01

    Phenylketonuria (PKU) is a disease caused by a deficiency of phenylalanine hydroxylase (PAH), resulting in an accumulation of phenylalanine (Phe) in the brain tissue, cerebrospinal fluid, and other tissues of PKU patients. Considering that high levels of Phe are associated with neurological dysfunction and that the mechanisms underlying the neurotoxicity in PKU remain poorly understood, the main objective of this study was to investigate the in vivo and in vitro effects of Phe on DNA damage, as determined by the alkaline comet assay. The results showed that, compared to control group, the levels of DNA migration were significantly greater after acute administration of Phe, p-chlorophenylalanine (p-Cl-Phe, an inhibitor of PAH), or a combination thereof in cerebral cortex and blood, indicating DNA damage. These treatments also provoked increase of carbonyl content. Additionally, when Phe or p-Cl-Phe was present in the incubation medium, we observed an increase in the frequency and index of DNA damage in the cerebral cortex and blood, without affecting lactate dehydrogenase (LDH) release. Our in vitro and in vivo findings indicate that DNA damage occurs in the cerebral cortex and blood of rats receiving Phe, suggesting that this mechanism could be, at least in part, responsible for the neurological dysfunction in PKU patients.

  16. Neonatal Screening of Inborn Errors of Metabolism Using Tandem Mass Spectrometry

    PubMed Central

    2003-01-01

    Executive Summary Objectives and Method The Medical Advisory Secretariat undertook a review of the evidence on the effectiveness and cost-effectiveness of using tandem mass spectrometer [MS/MS] for the neonatal screening of inborn errors of metabolism [IEM]. The review is based on two systematic reviews commissioned by the National Health Services (United Kingdom) and relevant research literature that was published after the completion of these two systematic reviews. A horizon scanning was conducted to determine the current status of neonatal screening programs in other national and international jurisdictions. The MAS also consulted with stakeholders including the laboratory branch, an expert in IEM at a pediatric hospital, MS/MS experts and a MS/MS manufacturer. Result Synthesis of information obtained from the above process showed that: Ontario is currently screening all newborns for phenylketonuria [PKU] and congenital hypothyroidism [CH] using the Guthrie method on dry blood spots obtained by heel prick before discharge from hospital. MS/MS can detect 25 IEMs in a single process on the same dry blood spot. Computer algorithms have been used to automate the MS/MS screening process to provide rapid throughputs of 400 samples or more per day. Screening for additional IEMs using MS/MS does not add significant cost to the program. MS/MS -based neonatal screening showed sensitivity of 100% and specificity of 83% to 99% depending on the IEM. The specificity of MS/MS in detecting PKU is significantly superior to that of the current Guthrie method and is therefore able to reduce the number of false positive results. For certain inborn errors of metabolism not currently screened, early detection and simple treatment could avoid early mortality and prevent or reduce mental retardation Using eligibility criteria recommended by the World Health Organization adapted to Ontario, a rating system was developed and applied to assess the IEMs recommended for inclusion in

  17. Normal vitamin D levels and bone mineral density among children with inborn errors of metabolism consuming medical food-based diets.

    PubMed

    Geiger, Katie E; Koeller, David M; Harding, Cary O; Huntington, Kathleen L; Gillingham, Melanie B

    2016-01-01

    A higher incidence of osteopenia is observed among children with inherited metabolic disorders (inborn errors of metabolism, or IEMs) who consume medical food-based diets that restrict natural vitamin D-containing food sources. We evaluated the vitamin D status of children with IEMs who live in the Pacific Northwest with limited sun exposure and determined whether bone mineral density (BMD) in children with phenylketonuria (PKU), the most common IEM, correlated with diet or biochemical markers of bone metabolism. We hypothesized that children with IEMs would have lower serum vitamin D concentrations than controls and that some children with PKU would have reduced bone mineralization. A retrospective record review of 88 patients with IEMs, and 445 children on unrestricted diets (controls) found the 25-hydroxyvitamin D concentrations were normal and not significantly different between groups (IEM patients, 27.1 ± 10.9; controls, 27.6 ± 11.2). Normal BMD at the hip or spine (-2 PKU. There was a correlation between lumbar spine BMD and dietary calcium intake. We saw no evidence of low serum vitamin D in our population of children with IEMs compared with control children. We also found no evidence for reduced BMD in children with PKU on specialized diets, but BMD was associated with calcium intake. Dietary intake of essential nutrients in medical food-based diets supports normal 25-hydroxyvitamin D levels and BMD in children with IEMs, including PKU. The risk of vitamin D deficiency among patients consuming a medical food-based diet is similar to the general population. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Evidence that L-carnitine and selenium supplementation reduces oxidative stress in phenylketonuric patients.

    PubMed

    Sitta, A; Vanzin, C S; Biancini, G B; Manfredini, V; de Oliveira, A B; Wayhs, C A Y; Ribas, G O S; Giugliani, L; Schwartz, I V D; Bohrer, D; Garcia, S C; Wajner, M; Vargas, C R

    2011-04-01

    It is well established that the involvement of reactive species in the pathophysiology of several neurological diseases, including phenylketonuria (PKU), a metabolic genetic disorder biochemically characterized by elevated levels of phenylalanine (Phe). In previous studies, we verified that PKU patients (treated with a protein-restricted diet supplemented with a special formula not containing L-carnitine and selenium) presented high lipid and protein oxidative damage as well as a reduction of antioxidants when compared to the healthy individuals. Our goal in the present study was to evaluate the effect of Phe-restricted diet supplemented with L-carnitine and selenium, two well-known antioxidant compounds, on oxidative damage in PKU patients. We investigated various oxidative stress parameters in blood of 18 treated PKU patients before and after 6 months of supplementation with a special formula containing L-carnitine and selenium. It was verified that treatment with L-carnitine and selenium was capable of reverting the lipid peroxidation, measured by thiobarbituric acid-reactive species, and the protein oxidative damage, measured by sulfhydryl oxidation, to the levels of controls. Additionally, the reduced activity of glutathione peroxidase was normalized by the antioxidant supplementation. It was also verified a significant inverse correlation between lipid peroxidation and L-carnitine blood levels as well as a significant positive correlation between glutathione peroxidase activity and blood selenium concentration. In conclusion, our results suggest that supplementation of L-carnitine and selenium is important for PKU patients since it could help to correct the oxidative stress process which possibly contributes, at least in part, to the neurological symptoms found in phenylketonuric patients.

  19. New PAH gene promoter KLF1 and 3'-region C/EBPalpha motifs influence transcription in vitro.

    PubMed

    Klaassen, Kristel; Stankovic, Biljana; Kotur, Nikola; Djordjevic, Maja; Zukic, Branka; Nikcevic, Gordana; Ugrin, Milena; Spasovski, Vesna; Srzentic, Sanja; Pavlovic, Sonja; Stojiljkovic, Maja

    2017-02-01

    Phenylketonuria (PKU) is a metabolic disease caused by mutations in the phenylalanine hydroxylase (PAH) gene. Although the PAH genotype remains the main determinant of PKU phenotype severity, genotype-phenotype inconsistencies have been reported. In this study, we focused on unanalysed sequences in non-coding PAH gene regions to assess their possible influence on the PKU phenotype. We transiently transfected HepG2 cells with various chloramphenicol acetyl transferase (CAT) reporter constructs which included PAH gene non-coding regions. Selected non-coding regions were indicated by in silico prediction to contain transcription factor binding sites. Furthermore, electrophoretic mobility shift assay (EMSA) and supershift assays were performed to identify which transcriptional factors were engaged in the interaction. We found novel KLF1 motif in the PAH promoter, which decreases CAT activity by 50 % in comparison to basal transcription in vitro. The cytosine at the c.-170 promoter position creates an additional binding site for the protein complex involving KLF1 transcription factor. Moreover, we assessed for the first time the role of a multivariant variable number tandem repeat (VNTR) region located in the 3'-region of the PAH gene. We found that the VNTR3, VNTR7 and VNTR8 constructs had approximately 60 % of CAT activity. The regulation is mediated by the C/EBPalpha transcription factor, present in protein complex binding to VNTR3. Our study highlighted two novel promoter KLF1 and 3'-region C/EBPalpha motifs in the PAH gene which decrease transcription in vitro and, thus, could be considered as PAH expression modifiers. New transcription motifs in non-coding regions will contribute to better understanding of the PKU phenotype complexity and may become important for the optimisation of PKU treatment.

  20. In vivo enzyme activity in inborn errors of metabolism

    SciTech Connect

    Thompson, G.N.; Walter, J.H.; Leonard, J.V.; Halliday, D. )

    1990-08-01

    Low-dose continuous infusions of (2H5)phenylalanine, (1-13C)propionate, and (1-13C)leucine were used to quantitate phenylalanine hydroxylation in phenylketonuria (PKU, four subjects), propionate oxidation in methylmalonic acidaemia (MMA, four subjects), and propionic acidaemia (PA, four subjects) and leucine oxidation in maple syrup urine disease (MSUD, four subjects). In vivo enzyme activity in PKU, MMA, and PA subjects was similar to or in excess of that in adult controls (range of phenylalanine hydroxylation in PKU, 3.7 to 6.5 mumol/kg/h, control 3.2 to 7.9, n = 7; propionate oxidation in MMA, 15.2 to 64.8 mumol/kg/h, and in PA, 11.1 to 36.0, control 5.1 to 19.0, n = 5). By contrast, in vivo leucine oxidation was undetectable in three of the four MSUD subjects (less than 0.5 mumol/kg/h) and negligible in the remaining subject (2 mumol/kg/h, control 10.4 to 15.7, n = 6). These results suggest that significant substrate removal can be achieved in some inborn metabolic errors either through stimulation of residual enzyme activity in defective enzyme systems or by activation of alternate metabolic pathways. Both possibilities almost certainly depend on gross elevation of substrate concentrations. By contrast, only minimal in vivo oxidation of leucine appears possible in MSUD.

  1. Post-Translational Incorporation of L-Phenylalanine into the C-Terminus of α-Tubulin as a Possible Cause of Neuronal Dysfunction

    PubMed Central

    Ditamo, Yanina; Dentesano, Yanela M.; Purro, Silvia A.; Arce, Carlos A.; Bisig, C. Gastón

    2016-01-01

    α-Tubulin C-terminus undergoes post-translational, cyclic tyrosination/detyrosination, and L-Phenylalanine (Phe) can be incorporated in place of tyrosine. Using cultured mouse brain-derived cells and an antibody specific to Phe-tubulin, we showed that: (i) Phe incorporation into tubulin is reversible; (ii) such incorporation is not due to de novo synthesis; (iii) the proportion of modified tubulin is significant; (iv) Phe incorporation reduces cell proliferation without affecting cell viability; (v) the rate of neurite retraction declines as level of C-terminal Phe incorporation increases; (vi) this inhibitory effect of Phe on neurite retraction is blocked by the co-presence of tyrosine; (vii) microtubule dynamics is reduced when Phe-tubulin level in cells is high as a result of exogenous Phe addition and returns to normal values when Phe is removed; moreover, microtubule dynamics is also reduced when Phe-tubulin is expressed (plasmid transfection). It is known that Phe levels are greatly elevated in blood of phenylketonuria (PKU) patients. The molecular mechanism underlying the brain dysfunction characteristic of PKU is unknown. Beyond the differences between human and mouse cells, it is conceivable the possibility that Phe incorporation into tubulin is the first event (or among the initial events) in the molecular pathways leading to brain dysfunctions that characterize PKU. PMID:27905536

  2. Phenylalanine hydroxylase: function, structure, and regulation.

    PubMed

    Flydal, Marte I; Martinez, Aurora

    2013-04-01

    Mammalian phenylalanine hydroxylase (PAH) catalyzes the rate-limiting step in the phenylalanine catabolism, consuming about 75% of the phenylalanine input from the diet and protein catabolism under physiological conditions. In humans, mutations in the PAH gene lead to phenylketonuria (PKU), and most mutations are mainly associated with PAH misfolding and instability. The established treatment for PKU is a phenylalanine-restricted diet and, recently, supplementation with preparations of the natural tetrahydrobiopterin cofactor also shows effectiveness for some patients. Since 1997 there has been a significant increase in the understanding of the structure, catalytic mechanism, and regulation of PAH by its substrate and cofactor, in addition to improved correlations between genotype and phenotype in PKU. Importantly, there has also been an increased number of studies on the structure and function of PAH from bacteria and lower eukaryote organisms, revealing an additional anabolic role of the enzyme in the synthesis of melanin-like pigments. In this review, we discuss these recent studies, which contribute to define the evolutionary adaptation of the PAH structure and function leading to sophisticated regulation for effective catabolic processing of phenylalanine in mammalian organisms.

  3. Women's Attitudes Regarding Prenatal Testing for a Range of Congenital Disorders of Varying Severity.

    PubMed

    Norton, Mary E; Nakagawa, Sanae; Kuppermann, Miriam

    2014-01-21

    Little is known about women's comparative attitudes towards prenatal testing for different categories of genetic disorders. We interviewed women who delivered healthy infants within the past year and assessed attitudes towards prenatal screening and diagnostic testing, as well as pregnancy termination, for Down syndrome (DS), fragile X (FraX), cystic fibrosis (CF), spinal muscular atrophy (SMA), phenylketonuria (PKU) and congenital heart defects (CHD). Ninety-five women aged 21 to 48 years participated, of whom 60% were Caucasian, 23% Asian, 10% Latina and 7% African American; 82% were college graduates. Ninety-five to ninety-eight percent indicated that they would have screening for each condition, and the majority would have amniocentesis (64% for PKU to 72% for SMA). Inclinations regarding pregnancy termination varied by condition: Whereas only 10% reported they would probably or definitely terminate a pregnancy for CHD, 41% indicated they would do so for DS and 62% for SMA. Most women in this cohort reported that they would undergo screening for all six conditions presented, the majority without the intent to terminate an affected pregnancy. These women were least inclined to terminate treatable disorders (PKU, CHD) versus those associated with intellectual disability (DS, FraX) and were most likely to terminate for SMA, typically lethal in childhood.

  4. A framework for assessing outcomes from newborn screening: on the road to measuring its promise.

    PubMed

    Hinton, Cynthia F; Homer, Charles J; Thompson, Alexis A; Williams, Andrea; Hassell, Kathryn L; Feuchtbaum, Lisa; Berry, Susan A; Comeau, Anne Marie; Therrell, Bradford L; Brower, Amy; Harris, Katharine B; Brown, Christine; Monaco, Jana; Ostrander, Robert J; Zuckerman, Alan E; Kaye, Celia; Dougherty, Denise; Greene, Carol; Green, Nancy S

    2016-08-01

    Newborn screening (NBS) is intended to identify congenital conditions prior to the onset of symptoms in order to provide early intervention that leads to improved outcomes. NBS is a public health success, providing reduction in mortality and improved developmental outcomes for screened conditions. However, it is less clear to what extent newborn screening achieves the long-term goals relating to improved health, growth, development and function. We propose a framework for assessing outcomes for the health and well-being of children identified through NBS programs. The framework proposed here, and this manuscript, were approved for publication by the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC). This framework can be applied to each screened condition within the Recommended Uniform Screening Panel (RUSP), recognizing that the data elements and measures will vary by condition. As an example, we applied the framework to sickle cell disease and phenylketonuria (PKU), two diverse conditions with different outcome measures and potential sources of data. Widespread and consistent application of this framework across state NBS and child health systems is envisioned as useful to standardize approaches to assessment of outcomes and for continuous improvement of the NBS and child health systems. Successful interventions for newborn screening conditions have been a driving force for public health newborn screening for over fifty years. Organizing interventions and outcome measures into a standard framework to systematically assess outcomes has not yet come into practice. This paper presents a customizable outcomes framework for organizing measures for newborn screening condition-specific health outcomes, and an approach to identifying sources and challenges to populating those measures. Published by Elsevier Inc.

  5. Simple and rapid analytical method for detection of amino acids in blood using blood spot on filter paper, fast-GC/MS and isotope dilution technique.

    PubMed

    Kawana, Shuichi; Nakagawa, Katsuhiro; Hasegawa, Yuki; Yamaguchi, Seiji

    2010-11-15

    A simple and rapid method for quantitative analysis of amino acids, including valine (Val), leucine (Leu), isoleucine (Ile), methionine (Met) and phenylalanine (Phe), in whole blood has been developed using GC/MS. In this method, whole blood was collected using a filter paper technique, and a 1/8 in. blood spot punch was used for sample preparation. Amino acids were extracted from the sample, and the extracts were purified using cation-exchange resins. The isotope dilution method using ²H₈-Val, ²H₃-Leu, ²H₃-Met and ²H₅-Phe as internal standards was applied. Following propyl chloroformate derivatization, the derivatives were analyzed using fast-GC/MS. The extraction recoveries using these techniques ranged from 69.8% to 87.9%, and analysis time for each sample was approximately 26 min. Calibration curves at concentrations from 0.0 to 1666.7 μmol/l for Val, Leu, Ile and Phe and from 0.0 to 333.3 μmol/l for Met showed good linearity with regression coefficients=1. The method detection limits for Val, Leu, Ile, Met and Phe were 24.2, 16.7, 8.7, 1.5 and 12.9 μmol/l, respectively. This method was applied to blood spot samples obtained from patients with phenylketonuria (PKU), maple syrup urine disease (MSUD), hypermethionine and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), and the analysis results showed that the concentrations of amino acids that characterize these diseases were increased. These results indicate that this method provides a simple and rapid procedure for precise determination of amino acids in whole blood.

  6. School performance in early and continuously treated phenylketonuria.

    PubMed

    Gassió, Rosa; Fusté, Eugenia; López-Sala, Anna; Artuch, Rafael; Vilaseca, María Antonia; Campistol, Jaume

    2005-10-01

    This study investigated the relationship between school performance, cognitive functions, and dietary control in a group of 26 early and continuously treated phenylketonuric patients, in comparison with 21 sex- and age-matched control subjects. The cognitive functions study included intelligence measurement, visual and auditory memory and auditory verbal learning abilities, attention, visuospatial, fine motor, language, and executive functions. Participants were asked about school performance. The indexes of dietary control for the first 6 years of life and for the 6 months before the study were calculated. The intelligence score was significantly lower in phenylketonuric patients (P < 0.0001). The percentage of patients with attention problems (P = 0.02), fine motor (P = 0.001) and executive dysfunctions (P = 0.013) was significantly higher than that for control subjects. Patients had more school problems than controls (P = 0.028). Intelligence score was also significantly lower in these patients (P = 0.046). The index of dietary control for the last 6 months was significantly higher than the index for the first 6 years of life, but only in the patients with school problems (P = 0.033). In conclusion, phenylketonuric patients presented more school problems than control subjects, probably related to the disturbed cognitive functions observed. The index of dietary control for the last 6 months yielded a close relationship with school performance.

  7. Psychiatric disorders in adolescent and young adult patients with phenylketonuria.

    PubMed

    Manti, Filippo; Nardecchia, Francesca; Chiarotti, Flavia; Carducci, Claudia; Carducci, Carla; Leuzzi, Vincenzo

    2016-01-01

    Psychiatric symptoms are a challenging aspect in adolescent and adult early treated phenylketonuric (ETPKU) patients. To assess the occurrence of psychiatric disorders we explored the presence of symptoms requiring intervention and further investigated the link between psychiatric disorders, the quality of biochemical control and cognitive functioning. Forty-six ETPKU patients (aged 12 to 44) and 30 age-matched healthy controls were subjected to cognitive and psychiatric assessment by means of self-report questionnaires and psychiatric interview. Psychiatric diagnoses, if detected, were made according to DSM-5 criteria. Concomitant IQ, historical and concurrent biochemical metabolic controls were included in the statistical analysis. Twenty-five out of 46 ETPKUs showed clinical scores on at least one scale of the psychiatric assessment (7/30 in controls); anxiety and withdrawal were the most frequent self-reported symptoms. Seventeen patients (and no controls) met criteria for a psychiatric diagnosis, most of them belonging to the Anxiety Disorders category. The occurrence of psychiatric symptoms was not associated with the life-long and concurrent quality of metabolic control but patients with good metabolic control (≤ 500 μM) in the first 11 years of life showed higher frequency of psychiatric diagnosis (Fisher's exact p=.0300). ETPKUs show a higher than normal vulnerability to psychiatric disorders, which cannot be explained by the usual biochemical alterations influencing intellectual outcome. Our data support the hypothesis that the burden of the disease acts as psychological stress for children and their families. Possible involvement of neuromediators in the pathogenesis of these complex symptoms requires further investigation. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Complete spectrum of PAH mutations in Tataria: presence of Slavic, Turkic and Scandinavian mutations.

    PubMed

    Kuzmin, A I; Eisensmith, R C; Goltsov, A A; Sergeeva, N A; Schwartz, E I; Woo, S L

    1995-01-01

    Phenylketonuria (PKU) is an autosomal recessive disorder associated with a deficiency of hepatic phenylalanine hydroxylase (PAH). Although the molecular lesions present in the PAH genes of PKU patients have previously been determined in several Slavic populations, little is known regarding the molecular basis of PKU in the non-Slavic populations of the former Soviet Union. Guthrie card samples from twenty-one classical PKU patients residing in the Tatarian Republic were examined by a combination of denaturing gradient gel electrophoresis and direct sequence analysis. Twelve patients were of Tatarian ancestry, five were of Russian ancestry, and four were of mixed Tatarian and Russian ancestry. Two of the Tatarian patients were related, sharing one mutant allele. The single major allele identified in this study was R408W/RFLP haplotype 2/VNTR 3, which was present on 11/14 or 78.6% of all mutant chromosomes of Slavic origin, but on only 10/27 or 37.0% of mutant chromosomes of Tatarian origin. This result suggests that this allele was introduced into central Asian populations during the eastward expansion of Slavs across the Eurasian landmass. A significant influence of Turkic peoples on Tatars can be inferred from the presence of R261Q. IVS10nt546g --> a, L48S, IVS2nt5g --> c and P281L, all of which are relatively common among Turks or have been observed in Mediterranean populations. Together, these alleles are present on 11/27 or 40.7% of all mutant chromosomes in ethnic Tatars. Surprisingly, the common Scandinavian mutation IVS12ntlg --> a was also present in Tataria, as was the delta agE221D222fs mutation found previously only in Denmark. Thus, some direct or indirect gene flow from Scandinavian into Tataria seems evident. Finally, the complete absence of PAH mutations previously observed in Oriental populations suggests that there was little gene flow into Tataria from Eastern Asia.

  9. Glycomacropeptide is a prebiotic that reduces Desulfovibrio bacteria, increases cecal short-chain fatty acids, and is anti-inflammatory in mice

    PubMed Central

    Sawin, Emily A.; De Wolfe, Travis J.; Aktas, Busra; Stroup, Bridget M.; Murali, Sangita G.; Steele, James L.

    2015-01-01

    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 putative prebiotic based on extensive glycosylation with sialic acid, galactose, and galactosamine. Our objective was to determine the prebiotic properties of GMP by characterizing cecal and fecal microbiota populations, short-chain fatty acids (SCFA), and immune responses. Weanling PKU (Pahenu2) and wild-type (WT) C57Bl/6 mice were fed isoenergetic AA, GMP, or casein diets for 8 wk. The cecal content and feces were collected for microbial DNA extraction to perform 16S microbiota analysis by Ion Torrent PGM sequencing. SCFA were determined by gas chromatography, plasma cytokines via a Bio-Plex Pro assay, and splenocyte T cell populations by flow cytometry. Changes in cecal and fecal microbiota are primarily diet dependent. The GMP diet resulted in a reduction from 30–35 to 7% in Proteobacteria, genera Desulfovibrio, in both WT and PKU mice with genotype-dependent changes in Bacteroidetes or Firmicutes. Cecal concentrations of the SCFA acetate, propionate, and butyrate were increased with GMP. The percentage of stimulated spleen cells producing interferon-γ (IFN-γ) was significantly reduced in mice fed GMP compared with casein. In summary, plasma concentrations of IFN-γ, TNF-α, IL-1β, and IL-2 were reduced in mice fed GMP. GMP is a prebiotic based on reduction in Desulfovibrio, increased SCFA, and lower indexes of inflammation compared with casein and AA diets in mice. Functional foods made with GMP may be beneficial in the management of PKU, obesity, and IBD. PMID:26251473

  10. Medical Problems in Obstetrics: Inherited Metabolic Disease.

    PubMed

    Murphy, Elaine

    2015-07-01

    An increasing number of women with rare inherited disorders of metabolism are becoming pregnant. Although, in general, outcomes for women and their children are good, there are a number of issues that need to be considered. Currently, limited specific guidance on the management of these conditions in pregnancy is available. Prepregnancy counselling with information on inheritance, options for reproduction, teratogenicity risk, potential impact on maternal health and long-term health of children should be offered. With appropriate specialist management, the teratogenic risk of conditions such as maternal phenylketonuria (PKU) can be eliminated, and the risk of metabolic decompensation in disorders of energy metabolism or intoxication significantly reduced. Multidisciplinary management, and close liaison between obstetricians and other specialists, is required for those women in whom there is cardiac, renal, respiratory, joint or other organ involvement.

  11. How Darwinian reductionism refutes genetic determinism.

    PubMed

    Rosoff, Philip M; Rosenberg, Alex

    2006-03-01

    Genetic determinism labels the morally problematical claim that some socially significant traits, traits we care about, such as sexual orientation, gender roles, violence, alcoholism, mental illness, intelligence, are largely the results of the operation of genes and not much alterable by environment, learning or other human intervention. Genetic determinism does not require that genes literally fix these socially significant traits, but rather that they constrain them within narrow channels beyond human intervention. In this essay we analyze genetic determinism in light of what is now known about the inborn error of metabolism phenylketonuria (PKU), which has for so long been the poster child 'simple' argument in favor of some form of genetic determinism. We demonstrate that this case proves the exact opposite of what it has been proposed to support and provides a strong refutation of genetic determinism in all its guises.

  12. Pregnancy in women with inherited metabolic disease

    PubMed Central

    2015-01-01

    An increasing number of women with rare inherited disorders of metabolism are becoming pregnant. Whilst, in general, outcomes for women and their children are good, there are issues that need to be considered. Due to the rarity of many conditions, there is limited specific guidance available on best management. Prepregnancy counselling with information on inheritance, options for reproduction, teratogenicity risk, potential impact on maternal health and long-term health of children should be offered. With appropriate specialist management, the teratogenic risk of conditions such as maternal phenylketonuria (PKU) can be eliminated, and the risk of metabolic decompensation in other disorders of intoxication or energy metabolism significantly reduced. Newer therapies, such as enzyme replacement therapy, appear to be safe in pregnancy, but specific advice should be sought. Multidisciplinary management, and close liaison between obstetricians and other specialists is required for women in whom there is cardiac, renal, respiratory, joint or other organ involvement. PMID:27512458

  13. Retroviral-mediated gene transfer of human phenylalanine hydroxylase into NIH 3T3 and hepatoma cells

    SciTech Connect

    Ledley, F.D.; Grenett, H.E.; McGinnis-Shelnutt, M.; Woo, S.L.C.

    1986-01-01

    Phenylketonuria (PKU) is caused by deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH). A full-length human PAH cDNA sequence has been inserted into pzip-neoSV(X), which is a retroviral vector containing the bacterial neo gene. The recombinant has been transfected into Psi2 cells, which provide synthesis of the retroviral capsid. Recombinant virus was detected in the culture medium of the transfected Psi2 cells, which is capable of transmitting the human PAH gene into mouse NIH 3T3 cells by infection leading to stable incorporation of the recombinant provirus. Infected cells express PAH mRNA, immunoreactive PAH protein, and exhibit pterin-dependent phenylaline hydroxylase activity. The recombinant virus is also capable of infecting a mouse hepatoma cell line that does not normal synthesize PAH. PAH activity is present in the cellular extracts and the entire hydroxylation system is reconstituted in the hepatoma cells infected with the recombinant viruses. Thus, recombinant viruses containing human PAH cDNA provide a means for introducing functional PAH into mammalian cells of hepatic origin and can potentially be introduced into whole animals as a model for somatic gene therapy for PKU.

  14. Adult human liver mesenchymal progenitor cells express phenylalanine hydroxylase.

    PubMed

    Baruteau, Julien; Nyabi, Omar; Najimi, Mustapha; Fauvart, Maarten; Sokal, Etienne

    2014-09-01

    Phenylketonuria (PKU) is one of the most prevalent inherited metabolic diseases and is accountable for a severe encephalopathy by progressive intoxication of the brain by phenylalanine. This results from an ineffective L-phenylalanine hydroxylase enzyme (PAH) due to a mutated phenylalanine hydroxylase (PAH) gene. Neonatal screening programs allow an early dietetic treatment with restrictive phenylalanine intake. This diet prevents most of the neuropsychological disabilities but remains challenging for lifelong compliance. Adult-derived human liver progenitor cells (ADHLPC) are a pool of precursors that can differentiate into hepatocytes. We aim to study PAH expression and PAH activity in a differenciated ADHLPC. ADHLPC were isolated from human hepatocyte primary culture of two different donors and differenciated under specific culture conditions. We demonstrated the high expression of PAH and a large increase of PAH activity in differenciated LPC. The age of the donor, the cellular viability after liver digestion and cryopreservation affects PAH activity. ADHLPC might therefore be considered as a suitable source for cell therapy in PKU.

  15. Regular exercise prevents oxidative stress in the brain of hyperphenylalaninemic rats.

    PubMed

    Mazzola, Priscila Nicolao; Terra, Melaine; Rosa, Andrea Pereira; Mescka, Caroline Paula; Moraes, Tarsila Barros; Piccoli, Bruna; Jacques, Carlos Eduardo; Dalazen, Giovana; Cortes, Marcelo Xavier; Coelho, Juliana; Dutra-Filho, Carlos Severo

    2011-12-01

    Phenylketonuria (PKU) is caused by deficiency of phenylalanine hydroxylase, leading to accumulation of phenylalanine and its metabolites. Clinical features of PKU patients include mental retardation, microcephaly, and seizures. Oxidative stress has been found in these patients, and is possibly related to neurophysiopatology of PKU. Regular exercise can leads to adaptation of antioxidant system, improving its capacity to detoxification reactive species. The aim of this study was to verify the effects of regular exercise on oxidative stress parameters in the brain of hyperphenylalaninemic rats. Animals were divided into sedentary (Sed) and exercise (Exe) groups, and subdivided into saline (SAL) and hyperphenylalaninemia (HPA). HPA groups were induced HPA through administration of alpha-methylphenylalanine and phenylalanine for 17 days, while SAL groups (n = 16-20) received saline. Exe groups conducted 2-week aerobic exercise for 20 min/day. At 18th day, animals were killed and the brain was homogenized to determine thiobarbituric acid reactives substances (TBA-RS) content, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities. Soleus muscles were collected to determine glycogen content as a marker of oxidative adaptation. Exe groups showed enhanced glycogen content. HPA condition caused an increase in TBA-RS and SOD, and reduces CAT and GPx. Exercise was able to prevent all changes seen in the HPA group, reaching control values, except for SOD activity. No changes were found in the ExeSAL group compared to SedSAL. Hyperphenylalaninemic rats were more responsive to the benefits provided by regular exercise. Physical training may be an interesting strategy to restore the antioxidant system in HPA.

  16. Adolescent development

    MedlinePlus

    Development - adolescent; Growth and development - adolescent ... During adolescence, children develop the ability to: Understand abstract ideas. These include grasping higher math concepts, and developing moral ...

  17. Developing Thinking; Developing Learning

    ERIC Educational Resources Information Center

    McGregor, Debra

    2006-01-01

    It is now recognised that thinking skills, such as problem-solving, analysis, synthesis, creativity and evaluation, can be nurtured and developed, and education professionals can play a significant role in shaping the way that children learn and think. As a result, schools are being encouraged to make greater use of thinking skills in lessons and…

  18. Toddler development

    MedlinePlus

    ... JavaScript. Toddlers are children ages 1 to 3. CHILD DEVELOPMENT THEORIES Cognitive (thought) development skills typical for toddlers ... care provider if you have questions about your child's development. PHYSICAL DEVELOPMENT The following are signs of expected ...

  19. An Economic Evaluation of Neonatal Screening for Inborn Errors of Metabolism Using Tandem Mass Spectrometry in Thailand

    PubMed Central

    Thiboonboon, Kittiphong; Leelahavarong, Pattara; Wattanasirichaigoon, Duangrurdee; Vatanavicharn, Nithiwat; Wasant, Pornswan; Shotelersuk, Vorasuk; Pangkanon, Suthipong; Kuptanon, Chulaluck; Chaisomchit, Sumonta; Teerawattananon, Yot

    2015-01-01

    Background Inborn errors of metabolism (IEM) are a rare group of genetic diseases which can lead to several serious long-term complications in newborns. In order to address these issues as early as possible, a process called tandem mass spectrometry (MS/MS) can be used as it allows for rapid and simultaneous detection of the diseases. This analysis was performed to determine whether newborn screening by MS/MS is cost-effective in Thailand. Method A cost-utility analysis comprising a decision-tree and Markov model was used to estimate the cost in Thai baht (THB) and health outcomes in life-years (LYs) and quality-adjusted life year (QALYs) presented as an incremental cost-effectiveness ratio (ICER). The results were also adjusted to international dollars (I$) using purchasing power parities (PPP) (1 I$ = 17.79 THB for the year 2013). The comparisons were between 1) an expanded neonatal screening programme using MS/MS screening for six prioritised diseases: phenylketonuria (PKU); isovaleric acidemia (IVA); methylmalonic acidemia (MMA); propionic acidemia (PA); maple syrup urine disease (MSUD); and multiple carboxylase deficiency (MCD); and 2) the current practice that is existing PKU screening. A comparison of the outcome and cost of treatment before and after clinical presentations were also analysed to illustrate the potential benefit of early treatment for affected children. A budget impact analysis was conducted to illustrate the cost of implementing the programme for 10 years. Results The ICER of neonatal screening using MS/MS amounted to 1,043,331 THB per QALY gained (58,647 I$ per QALY gained). The potential benefits of early detection compared with late detection yielded significant results for PKU, IVA, MSUD, and MCD patients. The budget impact analysis indicated that the implementation cost of the programme was expected at approximately 2,700 million THB (152 million I$) over 10 years. Conclusion At the current ceiling threshold, neonatal screening using MS

  20. Web-based newborn screening system for metabolic diseases: machine learning versus clinicians.

    PubMed

    Chen, Wei-Hsin; Hsieh, Sheau-Ling; Hsu, Kai-Ping; Chen, Han-Ping; Su, Xing-Yu; Tseng, Yi-Ju; Chien, Yin-Hsiu; Hwu, Wuh-Liang; Lai, Feipei

    2013-05-23

    A hospital information system (HIS) that integrates screening data and interpretation of the data is routinely requested by hospitals and parents. However, the accuracy of disease classification may be low because of the disease characteristics and the analytes used for classification. The objective of this study is to describe a system that enhanced the neonatal screening system of the Newborn Screening Center at the National Taiwan University Hospital. The system was designed and deployed according to a service-oriented architecture (SOA) framework under the Web services .NET environment. The system consists of sample collection, testing, diagnosis, evaluation, treatment, and follow-up services among collaborating hospitals. To improve the accuracy of newborn screening, machine learning and optimal feature selection mechanisms were investigated for screening newborns for inborn errors of metabolism. The framework of the Newborn Screening Hospital Information System (NSHIS) used the embedded Health Level Seven (HL7) standards for data exchanges among heterogeneous platforms integrated by Web services in the C# language. In this study, machine learning classification was used to predict phenylketonuria (PKU), hypermethioninemia, and 3-methylcrotonyl-CoA-carboxylase (3-MCC) deficiency. The classification methods used 347,312 newborn dried blood samples collected at the Center between 2006 and 2011. Of these, 220 newborns had values over the diagnostic cutoffs (positive cases) and 1557 had values that were over the screening cutoffs but did not meet the diagnostic cutoffs (suspected cases). The original 35 analytes and the manifested features were ranked based on F score, then combinations of the top 20 ranked features were selected as input features to support vector machine (SVM) classifiers to obtain optimal feature sets. These feature sets were tested using 5-fold cross-validation and optimal models were generated. The datasets collected in year 2011 were used as

  1. Elevated phenylalanine on newborn screening: follow-up testing may reveal undiagnosed galactosaemia.

    PubMed

    Shakespeare, Lynette; Downing, Melanie; Allen, Joyce; Casbolt, Ann-Marie; Ellin, Sheila; Maloney, Martin; Race, Gillian; Bonham, Jim

    2010-11-01

    Introduction Newborn screening for phenylketonuria (PKU) can reveal other conditions which lead to an increased blood spot phenylalanine (Phe) concentration. We have investigated the proportion of blood spot samples that gave a positive screen due to clinically significant conditions other than PKU, compared the positive predictive value (PPV) of our referral Phe cut-off with that recommended by the UK Newborn Screening Programme Centre (UKNSPC) (>210 and >240 μmol/L, respectively) and evaluated the effectiveness of reflex testing for galactosaemia using a lower blood spot Phe cut-off concentration of 130 μmol/L. All blood spot samples that screened positive, for an increased Phe concentration, between April 2001 and March 2008, were identified from the records of the Sheffield Newborn Screening Laboratory and the diagnoses noted. In addition, all cases of galactosaemia detected in or notified to our screening laboratory within this time were also examined and the screened Phe concentrations compared. Out of 438,674 babies who were screened, 67 had Phe concentration >210 μmol/L (15 per 100,000). Of these, 40 had PKU or persistent hyperphenylalaninaemia with a Phe concentration identified by screening between 270 and 2350 μmol/L. A further 11 were diagnosed with another clinically significant disorder: galactosaemia (n = 8), biopterin defects (n = 2), tyrosinaemia Type 1 (n = 1). In addition, 16 had transient elevations in Phe. In total, nine cases of galactosaemia were identified, of whom, three had Phe concentrations <240 μmol/L with one asymptomatic individual having a concentration <210 μmol/L. Adoption of the UKNSPC recommended cut-off (>240 μmol/L) will not affect the detection rate of classical PKU, but will improve the PPV from 76% to 80%. The use of a lower cut-off (130 μmol/L) for reflex galactosaemia testing enables the timely identification of asymptomatic cases that benefit particularly from early treatment, without prompting any unnecessary

  2. Web-Based Newborn Screening System for Metabolic Diseases: Machine Learning Versus Clinicians

    PubMed Central

    Chen, Wei-Hsin; Hsu, Kai-Ping; Chen, Han-Ping; Su, Xing-Yu; Tseng, Yi-Ju; Chien, Yin-Hsiu; Hwu, Wuh-Liang; Lai, Feipei

    2013-01-01

    Background A hospital information system (HIS) that integrates screening data and interpretation of the data is routinely requested by hospitals and parents. However, the accuracy of disease classification may be low because of the disease characteristics and the analytes used for classification. Objective The objective of this study is to describe a system that enhanced the neonatal screening system of the Newborn Screening Center at the National Taiwan University Hospital. The system was designed and deployed according to a service-oriented architecture (SOA) framework under the Web services .NET environment. The system consists of sample collection, testing, diagnosis, evaluation, treatment, and follow-up services among collaborating hospitals. To improve the accuracy of newborn screening, machine learning and optimal feature selection mechanisms were investigated for screening newborns for inborn errors of metabolism. Methods The framework of the Newborn Screening Hospital Information System (NSHIS) used the embedded Health Level Seven (HL7) standards for data exchanges among heterogeneous platforms integrated by Web services in the C# language. In this study, machine learning classification was used to predict phenylketonuria (PKU), hypermethioninemia, and 3-methylcrotonyl-CoA-carboxylase (3-MCC) deficiency. The classification methods used 347,312 newborn dried blood samples collected at the Center between 2006 and 2011. Of these, 220 newborns had values over the diagnostic cutoffs (positive cases) and 1557 had values that were over the screening cutoffs but did not meet the diagnostic cutoffs (suspected cases). The original 35 analytes and the manifested features were ranked based on F score, then combinations of the top 20 ranked features were selected as input features to support vector machine (SVM) classifiers to obtain optimal feature sets. These feature sets were tested using 5-fold cross-validation and optimal models were generated. The datasets

  3. Consumerism & Development.

    ERIC Educational Resources Information Center

    Ockenden, Sandy

    1991-01-01

    This material asks social studies students in Canada to recognize the implications of the lifestyles of citizens in developed countries, and the power that consumers have to create change for a better world, to be agents of positive development. Development is seen as a four faceted process. This model implies that development is an approach to…

  4. Management Development.

    DTIC Science & Technology

    1972-12-01

    and aid the manager In defining a plan for self development. Most Illustrative Is the Talent Development Program offered by General Electric (Storey...results of game training. Training and Development Journal, 1967, 21(4), 26-37. Storey, W. D., & Baker, B. L. Talent development program. Ossining, N.Y

  5. Organization Development

    ERIC Educational Resources Information Center

    Huse, Edgar F.

    1978-01-01

    Organization Development (OD) is the application of behavioral-science knowledge to enhance an organization's effectiveness and efficiency. This article discusses the evolution of organization development, the basic components of an OD program, typologies of OD interventions, problems with organization development, and organization development in…

  6. Biochemical screening of 504,049 newborns in Denmark, the Faroe Islands and Greenland--experience and development of a routine program for expanded newborn screening.

    PubMed

    Lund, Allan Meldgaard; Hougaard, David Michael; Simonsen, Henrik; Andresen, Brage Storstein; Christensen, Mette; Dunø, Morten; Skogstrand, Kristin; Olsen, Rikke K J; Jensen, Ulrich Glümer; Cohen, Arieh; Larsen, Nanna; Saugmann-Jensen, Peter; Gregersen, Niels; Brandt, Niels Jacob; Christensen, Ernst; Skovby, Flemming; Nørgaard-Pedersen, Bent

    2012-11-01

    Expanded newborn screening for selected inborn errors of metabolism (IEM) in Denmark, the Faroe Islands and Greenland was introduced in 2002. We now present clinical, biochemical, and statistical results of expanded screening (excluding PKU) of 504,049 newborns during nine years as well as diagnoses and clinical findings in 82,930 unscreened newborns born in the same period. The frequencies of diagnoses made within the panel of disorders screened for are compared with the frequencies of the disorders in the decade preceding expanded newborn screening. The expanded screening was performed as a pilot study during the first seven years, and the experience obtained during these years was used in the development of the routine neonatal screening program introduced in 2009. Methods for screening included tandem mass spectrometry and an assay for determination of biotinidase activity. A total of 310 samples from 504,049 newborns gave positive screening results. Of the 310 results, 114 were true positive, including results from 12 newborns in which the disease in question was subsequently diagnosed in their mothers. Thus, the overall frequency of an IEM in the screening panel was 1:4942 (mothers excluded) or 1:4421 (mothers included). The false positive rate was 0.038% and positive predictive value 37%. Overall specificity was 99.99%. All patients with true positive results were followed in The Center for Inherited Metabolic Disorders in Copenhagen, and the mean follow-up period was 45 months (range 2109 months). There were no deaths among the 102 children, and 94% had no clinically significant sequelae at last follow-up. Our study confirms the higher frequency of selected IEM after implementation of expanded newborn screening and suggests an improved outcome for several disorders. We argue that newborn screening for these disorders should be standard of care, though unresolved issues remain, e.g. about newborns with a potential for remaining asymptomatic throughout life

  7. Technology Development.

    ERIC Educational Resources Information Center

    Gomory, Ralph E.

    1983-01-01

    The evolutionary character and complexity of technological development is discussed, focusing on the steam engine and computer as examples. Additional topics include characteristics of science/technology, cultural factors in technological development, technology transfer, and problems in technological organization. (JN)

  8. Technology Development.

    ERIC Educational Resources Information Center

    Gomory, Ralph E.

    1983-01-01

    The evolutionary character and complexity of technological development is discussed, focusing on the steam engine and computer as examples. Additional topics include characteristics of science/technology, cultural factors in technological development, technology transfer, and problems in technological organization. (JN)

  9. Sustainable Development.

    ERIC Educational Resources Information Center

    Auerbach, Raymond

    1994-01-01

    Discusses South African national development priorities, sustainable development, and the future of agriculture and presents three scenarios of possible national action: production for sale and export, household food security, and conservation of natural resources. (MKR)

  10. Preschooler development

    MedlinePlus

    ... little differently. If you are concerned about your child's development, talk to your child's health care provider. PHYSICAL ... and the A.D.A.M. Editorial team. Child Development Read more Latest Health News Read more Health ...

  11. Speech Development

    MedlinePlus

    ... able to assess your child’s speech production and language development and make appropriate therapy recommendations. It is also ... pathologist should consistently assess your child’s speech and language development, as well as screen for hearing problems (with ...

  12. Sustainable Development.

    ERIC Educational Resources Information Center

    Auerbach, Raymond

    1994-01-01

    Discusses South African national development priorities, sustainable development, and the future of agriculture and presents three scenarios of possible national action: production for sale and export, household food security, and conservation of natural resources. (MKR)

  13. Developer Network

    SciTech Connect

    2012-08-21

    NREL's Developer Network, developer.nrel.gov, provides data that users can access to provide data to their own analyses, mobile and web applications. Developers can retrieve the data through a Web services API (application programming interface). The Developer Network handles overhead of serving up web services such as key management, authentication, analytics, reporting, documentation standards, and throttling in a common architecture, while allowing web services and APIs to be maintained and managed independently.

  14. [Evaluation of the usefulness for neonatal mass screening in light of 35 years personal experience].

    PubMed

    Bozkowa, K; Cabalska, B; Radomyska, B; Ołtarzewski, M; Lenartowska, I

    1999-01-01

    The results and the significance of neonatal mass-screening programmes for inborn errors of metabolism, conducted by the National Research Institute of Mother and Child (NRIMC), are discussed. As the first in Poland, in 1964, mass-screening for phenylketonuria (PKU) was introduced. The BIA-Guthrie test was used. Other Guthrie tests (GBIA) were applied in homocystinuria, tyrosinemia, histidinemia and leucinosis (Maple Syrup Urine Disease-MSUD). In the middle of the 60. the Beutler and Baluda test was introduced for galactosaemia, as well as the Efron urine test in infant screening for different inborn errors of metabolism. In the middle of the 70., neonatal mass-screening for cystic fibrosis (CF, mucoviscidosis) was started. Meconium tests and the sweat test with ion selective chloride electrode were used. Apart from inborn errors of metabolism, we also introduced a screening programme for neuroblastoma in which vaniline mandelic acid (VMA) in urine was estimated and for congenital hypothyroidism were TSH level was assessed. The results of screening are shown in the tables and in the figures. In our opinion the best clinical results are obtained with screening for congenital hypothyroidism and for PKU, since very early detection and treatment in these diseases prevents severe mental retardation. We therefore consider that both these screening programmes should be treated as obligatory examinations in all neonates. Taking into consideration the fact that there are different types of hyperhenylalaninemias, the principles of differential diagnosis are discussed. Molecular genetic investigations, carried out in the NRIMC Department of Genetics proved to be a very important procedure in the verification of diagnosis of different mutations. The authors also discuss the problem of dietary treatment duration in PKU. In our opinion the hypophenyloalanine diet regimen in girls, should not be discontinued during adolescence, since there is the problem of maternal PKU and the

  15. Career Development.

    ERIC Educational Resources Information Center

    1996

    This document consists of four papers presented during a symposium on career development moderated by David Bjorkquist at the 1996 conference of the Academy of Human Resource Development (AHRD). "A Mentoring Model for Career Development" (Mary Finnegan) describes a study that created a model based on the assumption that mentoring is an essential…

  16. Teacher Development.

    ERIC Educational Resources Information Center

    1997

    Eight conference papers on language teacher development are presented, including: "Mosaics of Teacher Development and Socialization" (Andrew Barfield, Paul A. Beaufait, Sean Conley, Tim Murphey, Katsura Haruko), a panel presentation on aspects of and experiments in teacher development; "Questions About Teaching? Answers from…

  17. Resume Development.

    ERIC Educational Resources Information Center

    Lorenzen, Elizabeth A.; And Others

    This paper presents a step-by-step guide for developing a resume as part of a job search campaign. The paper presents the following information: purposes of the resume; steps in resume development; resume formats; resume headings; and some "do's and some "don't's." The paper also includes a list of 161 action verbs for use in resume development, a…

  18. Faculty Development.

    ERIC Educational Resources Information Center

    Gillan, Bob, Ed.; McFerrin, Karen, Ed.

    This document contains the following papers on faculty development and technology: "Involving Faculty in Faculty Development" (Kristine Blair and Dan Madigan); "Technology Use in Higher Education: A Faculty Development Model" (Jessica Kahn); "A Faculty of Education as a Community of Learners: Growing to Meet the Demands of…

  19. An Efficient Trio-Based Mini-Haplotyping Method for Genetic Diagnosis of Phenylketonuria

    PubMed Central

    Talebi, Saeed; Entezam, Mona; Mohajer, Neda; Kazemi-sefat, Golnaz-Ensieh; Razipour, Masoumeh; Ahmadloo, Somayeh; Setoodeh, Aria; Keramatipour, Mohammad

    2016-01-01

    Objective The phenylalanine hydroxylase (PAH) locus has high linkage disequilibrium. Haplotypes related to this locus may thus be considered sufficiently informative for genetic diagnosis and carrier screening using multi-allelic markers. In this study, we present an efficient method for haplotype analysis of PAH locus using multiplexing dyes. In addition, we explain how to resolve the dye shift challenge in multiplex short tandem repeat (STR) genotyping. Materials and Methods One hundred family trios were included in this descriptive study. The forward primer of a tetra-nucleotide STR and the reverse primer of a variable number tandem repeat (VNTR) were labeled with three different non-overlapping dyes 5-carboxyfluorescein (FAM), 6-carboxy-N,N,N’,N’-tetramethylrhodamine (HEX) and 6-carboxy-N,N,N’,N’-tetramethylrhodamine (TAMRA). The polymerase chain reaction (PCR) products from each family trio were multiplexed for capillary electrophoresis and results were analyzed using Peak Scanner software. Results Multiplexing trio products decreased the cost significantly. The TAMRA labeled products had a significant predictable shift (migrated at a slower electrophoretic rate) relative to the HEX and FAM labeled products. Through our methodology we achieve, the less inter-dye shift than intra-dye shift variance. Correcting the dye shift in the labeled products, according to the reference allele size, significantly decreased the inter-dye variability (P<0.001). Conclusion Multiplexing trio products helps to detect and resolve the dye shift accurately in each family, which otherwise would result in diagnostic error. The dye system of FAM, HEX and TAMRA is more feasible and cheaper than other dye systems. PMID:27540528

  20. A resolution designating December 3, 2014, as "National Phenylketonuria Awareness Day".

    THOMAS, 113th Congress

    Sen. Isakson, Johnny [R-GA

    2014-11-20

    Senate - 12/03/2014 Resolution agreed to in Senate without amendment and with a preamble by Unanimous Consent. (All Actions) Tracker: This bill has the status Agreed to in SenateHere are the steps for Status of Legislation: