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BACKGROUND: A subset of patients with phenylketonuria benefit from treatment with tetrahydrobiopterin (BH4), although there is no consensus on the definition of BH4 responsiveness. The aim of this study therefore was to gain insight into the definitions of long-term BH4 responsiveness being used around the world. METHODS: We performed a web-based survey targeting healthcare professionals involved in the treatment of PKU patients. Data were analysed according to geographical region (Europe, USA/Canada, other). RESULTS: We analysed 166 responses. Long-term BH4 responsiveness was commonly defined using natural protein tolerance (95.6%), improvement of metabolic control (73.5%) and increase in quality of life (48.2%). When a specific value for a reduction in phenylalanine concentrations was reported (n = 89), 30% and 20% were most frequently used as cut-off values (76% and 19% of respondents, respectively). When a specific relative increase in natural protein tolerance was used to define long-term BH4 responsiveness (n = 71), respondents most commonly reported cut-off values of 30% and 100% (28% of respondents in both cases). Respondents from USA/Canada (n = 50) generally used less strict cut-off values compared to Europe (n = 96). Furthermore, respondents working within the same center answered differently. CONCLUSION: The results of this study suggest a very heterogeneous situation on the topic of defining long-term BH4 responsiveness, not only at a worldwide level but also within centers. Developing a strong evidence- and consensus-based definition would improve the quality of BH4 treatment.
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Biopterinas/análogos & derivados , Fenilalanina/genética , Fenilcetonúrias/tratamento farmacológico , Biopterinas/efeitos adversos , Biopterinas/uso terapêutico , Canadá/epidemiologia , Europa (Continente)/epidemiologia , Humanos , Fenilalanina/sangue , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/sangue , Fenilcetonúrias/epidemiologia , Fenilcetonúrias/patologia , Estados Unidos/epidemiologiaRESUMO
An amendment to this paper has been published and can be accessed via the original article.
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BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. MAIN BODY: In 2017 the first European PKU Guidelines were published. These guidelines contained evidence based and/or expert opinion recommendations regarding diagnosis, treatment and care for patients with PKU of all ages. This manuscript is a supplement containing the practical application of the dietary treatment. CONCLUSION: This handbook can support dietitians, nutritionists and physicians in starting, adjusting and maintaining dietary treatment.
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Fenilalanina Hidroxilase , Fenilcetonúrias , Dieta , Humanos , Fenilalanina , TirosinaRESUMO
INTRODUCTION: Inborn errors of tetrahydrobiopterin (BH4) biosynthesis or recycling are a group of very rare neurometabolic diseases. Following growing awareness and improved availability of drug treatment the number of patients with BH4 disorders reaching adulthood is constantly increasing. Pregnancy care of patients with these disorders is therefore a new challenge for clinicians. METHODS: This retrospective study summarises for the first time clinical and biochemical monitoring data of 16 pregnancies in seven women with different disorders of BH4 metabolism and evaluates treatment regimens before and during pregnancy in relation to the obstetrical outcome and paediatric follow-up. RESULTS: Worsening of pre-existing neurological symptoms or occurrence of new symptoms during pregnancy was not observed in most of the cases. Treatment regimens remained mostly unchanged. Pregnancies were not complicated by disease-specific features. Organ abnormalities, miscarriage, prematurity, IUGR and chromosomal changes were occasionally reported, without showing any association with the standard drug treatment for BH4 deficiencies. CONCLUSION: Although our data on 16 pregnancies in seven patients did not present any association of standard drug treatment with an increased rate of pregnancy complications, abnormal obstetrical or paediatric outcome, an intensive clinical and biochemical supervision by a multidisciplinary team before, during and after the pregnancy in any BH4 deficiency is essential since available data on pregnancies in patients with BH4 deficiencies is limited.
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Biopterinas/análogos & derivados , Fenilcetonúrias/tratamento farmacológico , Complicações na Gravidez/etiologia , Resultado da Gravidez , Adolescente , Adulto , Biopterinas/uso terapêutico , Feminino , Humanos , Recém-Nascido , Gravidez , Complicações na Gravidez/prevenção & controle , Estudos Retrospectivos , Adulto JovemRESUMO
Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.
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Fenilcetonúrias/diagnóstico , Fenilcetonúrias/terapia , Guias de Prática Clínica como Assunto , Europa (Continente) , HumanosRESUMO
Pyruvate dehydrogenase complex (PDHc) defect is a well-known cause of mitochondrial disorders (MD) with at least six responsible genes (PDHA1, PDHB, DLAT, DLD, PDHX, PDP1). The aim of this work was to assess the diagnostic value of biochemical methods in recognition of PDHc defect in Polish patients with suspicion of MD. In the first step, Western blot of the E1α subunit was performed on 86 archive muscle bioptates with suspicion of MD. In the second step, Sanger PDHA1 sequencing was performed in 21 cases with low E1α expression. In the third step, 7 patients with negative results of PDHA1 sequencing were subjected to whole-exome sequencing (WES). This protocol revealed 4 patients with PDHA1 and one with DLD mutations. Four additional probands were diagnosed outside the protocol (WES or Sanger sequencing). The molecular characterization of PDHc defect was conducted in a total of 9 probands: 5 according to and 4 off the protocol. Additionally, two affected relatives were recognized by a family study. Altogether we identified seven different PDHA1 changes, including two novel variants [c.464T > C (p.Met155Thr) and c.856_859dupACTT (p.Arg288Leufs*10)] and one DLD variant. The lactate response to glucose load in the PDHA1 subset was compared to a subset of non PDHc-related MD. Opposite responses were observed, with an increase of 23% and decrease of 27%, respectively. The results show that determining lactate response to glucose load and muscle E1α expression may contribute to distinguishing PDHc-related and other MD, however, WES is becoming the method of choice for MD diagnostics.
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INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Doenças Autoimunes/terapia , Aberrações Cromossômicas , Gerenciamento Clínico , Gastroenteropatias/terapia , Fenilalanina/sangue , Fenilcetonúrias/terapia , Adolescente , Adulto , Doenças Autoimunes/sangue , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico , Biopterinas/análogos & derivados , Biopterinas/uso terapêutico , Criança , Pré-Escolar , Consanguinidade , Dieta , Europa (Continente) , Feminino , Gastroenteropatias/sangue , Gastroenteropatias/complicações , Gastroenteropatias/diagnóstico , Humanos , Lactente , Masculino , Fenilcetonúrias/sangue , Fenilcetonúrias/complicações , Fenilcetonúrias/diagnóstico , Gravidez , Estudos Retrospectivos , TurquiaRESUMO
BACKGROUND: There appears little consensus concerning protein requirements in phenylketonuria (PKU). METHODS: A questionnaire completed by 63 European and Turkish IMD centres from 18 countries collected data on prescribed total protein intake (natural/intact protein and phenylalanine-free protein substitute [PS]) by age, administration frequency and method, monitoring, and type of protein substitute. Data were analysed by European region using descriptive statistics. RESULTS: The amount of total protein (from PS and natural/intact protein) varied according to the European region. Higher median amounts of total protein were prescribed in infants and children in Northern Europe (n=24 centres) (infants <1 year, >2-3g/kg/day; 1-3 years of age, >2-3 g/kg/day; 4-10 years of age, >1.5-2.5 g/kg/day) and Southern Europe (n=10 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, 2 g/kg/day; 4-10 years of age, 1.5-2 g/kg/day), than by Eastern Europe (n=4 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, >2-2.5 g/kg/day; 4-10 years of age, >1.5-2 g/kg/day) and with Western Europe (n=25 centres) giving the least (infants <1 year, >2-2.5 g/kg/day, 1-3 years of age, 1.5-2 g/kg/day; 4-10 years of age, 1-1.5 g/kg/day). Total protein prescription was similar in patients aged >10 years (1-1.5 g/kg/day) and maternal patients (1-1.5 g/kg/day). CONCLUSIONS: The amounts of total protein prescribed varied between European countries and appeared to be influenced by geographical region. In PKU, all gave higher than the recommended 2007 WHO/FAO/UNU safe levels of protein intake for the general population.
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Aminoácidos/administração & dosagem , Caseínas/administração & dosagem , Proteínas Alimentares/administração & dosagem , Suplementos Nutricionais , Fragmentos de Peptídeos/administração & dosagem , Fenilcetonúrias/dietoterapia , Adulto , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fenilalanina , Inquéritos e Questionários , Turquia , Organização Mundial da SaúdeRESUMO
BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.
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Gerenciamento Clínico , Educação em Saúde/métodos , Inquéritos Epidemiológicos , Terapia Nutricional/métodos , Fenilcetonúrias/dietoterapia , Adolescente , Adulto , Criança , Aconselhamento/educação , Dieta , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Pais/educação , Cooperação do Paciente , Médicos , Projetos Piloto , Adulto JovemRESUMO
Common inborn errors of metabolism treated by low natural protein diets [amino acid (AA) disorders, organic acidemias and urea cycle disorders] are responsible for a collection of diverse clinical symptoms, each condition presenting at different ages with variable severity. Precursor-free or essential L-AAs are important in all these conditions. Optimal long-term outcome depends on early diagnosis and good metabolic control, but because of the rarity and severity of conditions, randomized controlled trials are scarce. In all of these disorders, it is commonly described that dietary adherence deteriorates from the age of 10 years onwards, at least in part representing the transition of responsibility from the principal caregivers to the patients. However, patients may have particular difficulties in managing the complexity of their treatment because of the impact of the condition on their neuropsychological profile. There are little data about their ability to self-manage their own diet or the success of any formal educational programs that may have been implemented. Trials conducted in non-phenylketonuria (PKU) patients are rare, and the development of specialist L-AAs for non-PKU AA disorders has usually shadowed that of PKU. There remains much work to be done in refining dietary treatments for all conditions and gaining acceptable dietary adherence and concordance, which is crucial for an optimal outcome.
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Aminoácidos/administração & dosagem , Dieta com Restrição de Proteínas , Suplementos Nutricionais , Doenças Metabólicas/dietoterapia , Cooperação do Paciente , Humanos , Comportamento Social , Distúrbios Congênitos do Ciclo da Ureia/dietoterapiaRESUMO
In recent years our understanding of the follow up policies for PKU has increased substantially. In particular, we now understand the importance of maintaining control of blood phenylalanine (phe) concentrations life-long to achieve the best long-term neuropsychological outcomes. The concordance with the follow up strategy remains a key challenge for the future, especially with respect to adolescents and young adults. The recent therapies could ease the burden of the dietary phe restriction for PKU patients and their families. The time may be right for revisiting the guidelines for follow up of PKU in order to address a number of important issues related to PKU management: promotion of breastfeeding to complementary feeding up to 2 years of age for prevention of early growth retardation and later overweight development, treatment advancements for metabolic control, blood phe and tyr variability, routine screening measures for nutritional biomarkers, neurocognitive and psychological assessments, bone pathology, understanding the challenges of compliance and transitioning into adulthood as an individual with PKU and addressing unmet needs in this population.
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Fenilcetonúrias/epidemiologia , Seguimentos , Humanos , Estado Nutricional , Fenilcetonúrias/sangue , Fenilcetonúrias/terapia , Guias de Prática Clínica como Assunto , Garantia da Qualidade dos Cuidados de Saúde , Resultado do TratamentoRESUMO
No reports are available about the course of pregnancies in women with tetrahydrobiopterin (BH(4)) deficiencies or the effects of treatment with BH(4), L-dopa/carbidopa and 5-hydroxytryptophan (5-OHTrp) on fetal development. We present for the first time the case of a mother with late-diagnosed mild form of 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, the course of her two subsequent pregnancies and clinical evaluation with follow-up of two offspring. In both pregnancies neurotransmitter precursors, as well as BH(4) dosages were increased proportionally to the mother's weight gain. To prevent maternal phenylketonuria (MPKU) syndrome, special attention was paid to increasing BH(4) dosages. Both pregnancies were complicated by threatened premature labour, by the mother's nicotinism and additionally, in the first pregnancy, by gestational diabetes mellitus and vaginitis. The first child was born in the 31st week of pregnancy with the symptoms of moderate intrauterine growth retardation (IUGR) and brain malformation in the form of right sided closed-lip schizencephaly with absence of septum pellucidum. Although the girl demonstrates mild left-sided hemiparesis, her psychological development at the age of 8 years is above average. The second child was born in the 37th week of pregnancy without brain anomalies and at the age of 5 years his psychomotor development is appropriate for the age. As the cause of brain malformations resulting in physical impairment in the first child is unknown, more data are essential to verify conclusions about the influence of the mother's BH(4) deficiency and the safety of her treatment for fetal development.
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Fenilcetonúrias/complicações , Fósforo-Oxigênio Liases/deficiência , Complicações na Gravidez/enzimologia , Adolescente , Biopterinas/análogos & derivados , Biopterinas/deficiência , Biopterinas/uso terapêutico , Criança , Pré-Escolar , Diagnóstico Tardio , Feminino , Humanos , Recém-Nascido , Masculino , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/tratamento farmacológico , Fenilcetonúrias/enzimologia , Gravidez , Complicações na Gravidez/tratamento farmacológico , Resultado da Gravidez , Adulto JovemRESUMO
BACKGROUND: Since the start of the European Society of Phenylketonuria and Allied Disorders Treated as Phenylketonuria (ESPKU) in 1987, an increasing number of parental organizations of member countries have joined. Treatment varies widely within Europe. A survey among professionals was done to determine goals and practice. METHOD: In 2005, a questionnaire was sent to professionals of member countries, addressing diagnostic and treatment procedures, numbers of patients necessary for a PKU centre, guidelines followed, numbers of patients treated and professionals involved in care, target phenylalanine concentrations, amount of protein prescribed, frequency of monitoring and clinical visits, need for follow-up of various clinical and biochemical data, the importance of various abnormalities, and definition of (non)compliance. RESULTS: Seventeen centres of 12 countries answered. Professionals of 13 countries could not be reached or did not respond. Differences in care were observed in many issues of care including target phenylalanine concentrations. Only few issues had general consensus. CONCLUSION: Not all countries were really active at ESPKU level. In the active countries, a professional could not always be contacted. Responses show that PKU care varies largely between European countries. Notwithstanding the large diversity on many issues of day-to-day care and therapeutic targets, results showed increasing consensus on some issues. The most important outcome of this questionnaire might be that the Scientific Advisory Committee of the ESPKU initiated meetings for professionals of different backgrounds taking care of PKU patients besides the already existing programme for parents, patients and delegates. Discussion among these professionals may improve quality of care.
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Comitês Consultivos , Fenilcetonúrias/terapia , Padrões de Prática Médica , Inquéritos e Questionários , Adolescente , Adulto , Comitês Consultivos/organização & administração , Comitês Consultivos/estatística & dados numéricos , Criança , Pré-Escolar , Europa (Continente) , Feminino , Pesquisas sobre Atenção à Saúde/métodos , Humanos , Lactente , Masculino , Guias de Prática Clínica como Assunto , Padrões de Prática Médica/estatística & dados numéricos , Qualidade da Assistência à Saúde , Sociedades Médicas/organização & administração , Adulto JovemRESUMO
BACKGROUND: Discontinuation of dietary therapy in adults with phenylketonuria can lead to neuropsychological abnormalities and emotional problems. The aim of our study was to assess the change in quality of life in adult patients returning to the diet and to define the reasons for failure in diet resumption. METHODS: Quality of life was assessed by means of the Psychological General Well-Being Index before study entry and subsequently after 3 and 9 months. Reasons for failure in diet resumption were analysed. RESULTS: 53 patients participated in the study. Initial quality of life assessment revealed severe distress in 17%, moderate distress in 28% and positive well-being in 55% of them. In the majority of patients with severe or moderate distress, improvement of subjective well-being was observed (especially in the domains of anxiety and depressiveness) if they managed to return to the diet (blood phenylalanine concentrations before study entry 0.78-1.62 mmol/L, mean 1.16 mmol/L; average blood phenylalanine concentration decrease by 0.42 mmol/L). Only 29 persons managed to maintain the diet for at least 3 months and only 10 participants finished the entire 9-month study protocol. Problems with dietary treatment while at work, the high cost of low-protein products and poor knowledge regarding proper diet were the most important factors responsible for failure in resumption of diet. CONCLUSION: Interpersonal differences exist between adult patients on relaxed diet, in some of whom quality of life often remains good, while others can suffer from severe emotional distress. Returning to diet increases quality of life in the majority of patients.
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Dieta com Restrição de Proteínas , Cooperação do Paciente , Fenilcetonúrias/dietoterapia , Qualidade de Vida , Adolescente , Adulto , Sintomas Afetivos/etiologia , Sintomas Afetivos/prevenção & controle , Biomarcadores/sangue , Dieta com Restrição de Proteínas/economia , Feminino , Custos de Cuidados de Saúde , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Fenilalanina/sangue , Fenilcetonúrias/sangue , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/psicologia , Polônia , Estudos Prospectivos , Índice de Gravidade de Doença , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Hereditary fructose intolerance (HFI) is caused by a deficiency of aldolase B due to mutations of the ALDOB gene. The disease poses diagnostic problems because of unspecific clinical manifestations. We report three cases of HFI all of whom had a chronic disease with neurological, nephrological or gastroenterological symptoms, whereas nutritional fructose intolerance, the pathognomonic sign of HFI, was apparent only in retrospect. In all patients a hypoglycosylated pattern of transferrin isoforms was found but was misinterpreted as a sign of CDG Ix. The correct diagnosis was achieved with marked delay (26, 36 and 24 months, respectively) by sequencing of the ALDOB gene two common mutations were identified on both alleles or on one (A150P/A175D, A150P/-, and A150P/A175D). The diagnosis was further supported by normalization of transferrin isoforms on a fructose-free diet. Data available in two patients showed that following the fructose restriction the type I pattern of carbohydrate-deficient transferrin detectable on fructose-containing diet disappeared after 3-4 weeks. These cases illustrate that in the first years of life HFI may show misleading variability in clinical presentation and that protein glycosylation analysis such as transferrin isofocusing may give important diagnostic clues. However, care should be taken not to misinterpret the abnormal results as CDG Ix as well as to remember that a normal profile does not exclude HFI due to the possibility of spontaneous fructose restriction in the diet. The presented data also emphasize the usefulness of ALDOB mutation screening for diagnosis of HFI.
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Intolerância à Frutose/diagnóstico , Intolerância à Frutose/genética , Frutose-Bifosfato Aldolase/genética , Transferrina/metabolismo , Diagnóstico Diferencial , Glicosilação , Humanos , MutaçãoRESUMO
Assessment of prefrontal brain cortex function can be helpful in treatment monitoring in patients with phenylketonuria. We aimed to assess the usefulness of computerized neuropsychological tests developed for handheld computers for this purpose. We observed worse test performance among persons with blood phenylalanine concentrations exceeding the recommended range. Use of handheld computers was assessed by patients and by doctors as interesting, not time-consuming and convenient. This method can be helpful during routine follow-up visits.
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Computadores de Mão , Testes Neuropsicológicos , Fenilalanina/metabolismo , Fenilcetonúrias/psicologia , Córtex Pré-Frontal/fisiopatologia , Adolescente , Adulto , Atitude Frente aos Computadores , Criança , Humanos , Fenilcetonúrias/fisiopatologiaRESUMO
Although the clinical heterogeneity of phenylketonuria (PKU) is well established, some questions about this condition remain. Subjects from the same family who share the same mutations in the phenylalanine hydroxylase (PAH) gene are expected to display similar disease courses, and therefore, when blood phenylalanine (Phe) levels, genotype and dietary treatment are all similar, differences in patient outcomes require additional explanations. The present authors describe two entirely different courses of late-detected PKU in two brothers with the same R408W/R111X genotype in the PAH gene. The older sibling was diagnosed with PKU at the age of 4 years and given treatment. His IQ was 97 at 26 years of age and moderate involvement of periventricular white matter was detected. The younger brother was diagnosed with PKU at the age of 11 months and given treatment. His IQ was < 25 at 22 years of age and severe dysmyelination changes were found by magnetic resonance imaging. The differences in the courses of the disease between these two brothers appear to be related to variations in their blood-brain barriers.
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Barreira Hematoencefálica/genética , Inteligência/genética , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/genética , Adulto , Encéfalo/patologia , Pré-Escolar , Genótipo , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Mutação , Fenótipo , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/patologia , Fatores de TempoRESUMO
Phenylketonuria (PKU), an autosomal recessive disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH), is clinically very heterogeneous. On molecular level more than 350 mutations in the PAH gene are known to date, which in different genotype combinations could account for biochemical and clinical variability. Mutations located in exon 3 coding for a part of the regulatory domain of the PAH enzyme cause classical PKU, mild PKU, and mild hyperphenylalaninemia (MHP). We describe the phenotypic effects of seven mutations in exon 3 of the PAH gene (R68G, R68S, R71H, S87R, P89S, I95F, and A104D). We propose that mutations located between amino acid positions 71 through 94 cause MHP.
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Fenilalanina Hidroxilase/genética , Fenilalanina/sangue , Fenilcetonúrias/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Éxons , Feminino , Genótipo , Humanos , Lactente , Masculino , Mutação de Sentido IncorretoRESUMO
Mutations in the genes encoding different parts of phenylalanine hydroxylation system cause persistent hyperphenylalaninaemia. The most frequent form of hyperphenylalaninaemia is caused by mutations in the PAH gene. The most common variant result from defect of tetrahydrobiopterin synthase. Mutations in the PAH and PTS genes in the Polish population are presented. Genotype--phenotype correlations are discussed.
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Mutação , Fenilcetonúrias/genética , Fósforo-Oxigênio Liases/genética , Ureo-Hidrolases/genética , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Genética Populacional , Genótipo , Humanos , Fenótipo , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/epidemiologia , Polônia/epidemiologiaRESUMO
Factors that make fluorine absorption and excretion easy or difficult from organisms of people and animals have been analysed. Fluorine is easily absorbed in presence of alimentary fat from soluble dust, from water environment, especially from an acid one. Compounds of calcium, magnesium, aluminium, microelements and various high protein diet make fluorine absorption difficult. Compounds that easily absorb fluorine, namely compounds of calcium, magnesium, aluminium, boron, phosphorus and vitamin C as well as climatic conditions (increasing perspiration) make fluorine excretion from organisms easy. Fluorine excretion is made difficult in the period of intensified mineralization and lactation processes. The age of the person is also important.