Background: 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. Methods: 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. Results: 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. Conclusions: Continuous care for adult PKU patients in a specialized outpatient clinic is successful, leading to good to satisfactory metabolic control and social outcomes. Uninterrupted good metabolic treatment throughout childhood and adolescence positively influences educational, professional and economic success in later life. Further effort in specialized paediatric and adult metabolic care is needed to prevent loss of follow-up and to support the recommended life-long treatment and/or care.

In an unselected series of mentally retarded children in the county of Västerbotten, Sweden, the annual incidence of children with severe mental retardation (SMR) (IQ &lt; 50) and alive at the age of one year decreased from 5.3 per 1,000 in 1959 - 1963 to 3.1 per 1,000 in 1967 -1970. This was mainly due to a decrease in the incidence of Down's syndrome. In parallel the proportion of mothers 35 years of age or more at the birth of the child decreased significantly. The prevalence of children with SMR in 1976 was 3.5 per 1,000. The main cause of the SMR was prenatal in 70 percent, perinatal in 8 percent and postnatal in 1 percent. The cause of the SMR was untraceable in 20 percent of the cases. Associated CNS-handicaps occurred in 52 percent of the cases. The annual incidence of mildly mentally retarded children (IQ 50 - 69) registered at the Bureau for Provision and Services for Mentally Retarded was 4.2 per 1,000 and the prevalence in 1979 was 3.8 per 1,000. The cause of the mild mental retardation (MMR) was untraceable in 43 percent. Prenatal causes were identified in as many as 43 percent. Perinatal causes were found in 7 percent and postnatal causes in 5 percent of the cases. Associated CNS-handicaps occurred in 30 percent of the cases.A syndrome of mental retardation with X-linked inheritance not recognized previously in Sweden was characterized clinically (mainly in boys, machro-orchidism, verbal disabilities) and cytogenetically (a fragile site on the X-chromosomes seen after cui turing in special folic acid deficient media) and found to have a prevalence of 6 percent in the population of severely mentally retarded boys. This makes this syndrome the next most common cause of SMR in boys after Down's syndrome. The chromosomal fragility was also identified in female carriers, which has implications for genetic counselling.Through identification of an untreated Phenylketonurie mother giving birth to five severely mentally retarded children, attention was focused on the risks for the fetus of the growing number of Phenylketonurie women identified neonatally and treated di etarily but untreated after the age of 10 - 15 years.Great improvement in intellectual and social ability was seen in a boy with phenylketonuria although the dietary treatment was not introduced until the age of eight years.Heavy irradiation of a fetus late in gestation caused mental retardation, microcephaly, stunted growth, and eye and teeth abnormalities, although such abnormalities are thought not to result from irradiation after 20 weeks of pregnancy. / <p>Endast s.1-71: sammanfattningen (kappan) i fulltexten.</p><p>Ej med i fulltexten s.72-145: 7 delar.</p> / digitalisering@umu

A Fenilcetonúria (PKU) é uma doença genética rara detectada pelo Programa Nacional de Triagem Neonatal (PNTN) por meio do "teste do pezinho". Uma vez diagnosticada e tratada precocemente com dieta específica e fórmula metabólica isenta de fenilalanina (Phe), a ocorrência de retardo mental é prevenida nestes pacientes. Mesmo sendo fornecida gratuitamente pelo Sistema Único de Saúde (SUS), mediante protocolo clínico, estima-se que os pacientes com PKU têm encontrado dificuldades de acesso à fórmula metabólica, recorrendo à via judicial para garantir a continuidade de seu tratamento. Não existem estudos sobre os fatores que levam os pacientes com PKU a ingressarem na justiça em busca do acesso ao seu tratamento, tampouco que caracterizem os argumentos utilizados pelos poderes públicos na tentativa de resolução desses conflitos. Objetivos: Este estudo constitui-se em uma das etapas de um projeto mais amplo intitulado "Acesso e Adesão ao Tratamento da Fenilcetonúria: avaliação da judicialização e do impacto médico e socioeconômico para os pacientes e sua famílias, e para o Sistema Único de Saúde do Rio Grande do Sul". Esta etapa teve por objetivo caracterizar o uso da via judicial para a obtenção do tratamento da PKU no Estado do Rio Grande do Sul (RS). Metodologia: estudo observacional e retrospectivo, baseado na análise de processos judiciais de indivíduos com PKU que ingressaram na justiça entre 2001 e 2010 e que solicitaram alguma forma de tratamento para essa doença. Foram analisados os dados correspondentes ao período compreendido entre a propositura da ação e a sentença. Resultados: foram identificados 20 processos ajuizados no período analisado, e que preenchiam os critérios de inclusão, sendo que o acesso integral aos documentos para análise só foi possível em 19 casos. Apenas 2/19 dos processos visavam à obtenção de terapias diferentes da fórmula metabólica. Em 17/19 dos processos havia relato de solicitação prévia de fornecimento do tratamento deferida pela Secretaria de Saúde – RS. Figuraram como réus o estado do RS (n=19), a União (n=1) e municípios (n=4). Os pedidos de antecipação de tutela foram deferidos em todos os processos. Ao final das análises, 18/19 dos processos possuíam sentenças, obrigando os réus a fornecerem os insumos solicitados. Conclusões: os dados sugerem a violação do direito à saúde e a interrupção do fornecimento do tratamento pelo Estado como as principais razões para o uso da via judicial. Há evidências ainda, de que problemas como gestão de estoque e processos licitatórios morosos contribuam para a judicialização da PKU no RS. Ao contrário do que acontece com outras doenças genéticas, no caso da PKU a busca pela via judicial visa à obtenção de um produto que já está incluído na política de assistência farmacêutica nacional, achado que sugere que falhas de gestão são um dos fatores desencadeantes da judicialização no país. / Phenylketonuria (PKU) is a rare genetic disease detected by the Brazilian National Neonatal Screening Program (PNTN) through the "heel-stick test". Once diagnosed and treated early with a specific diet and metabolic phenylalanine-free formula (Phe), the occurrence of mental retardation is prevented in these patients. Even being provided free of charge by the Public Health System through National Guidelines, it is estimated that patients with PKU have found difficulty in obtaining the metabolic formula, resorting to the courts to ensure the continuity of their treatment. There are no studies on the factors that lead patients with PKU to file lawsuits in search of justice to have access to their treatment, nor that characterize the arguments used by the government in an attempt to solve these conflicts. Objectives: This study constitutes one of the steps of a broader project entitled "Access and Adherence to Phenylketonuria Treatment: evaluation of judicialization and the medical and socio-economic impact for patients and their families, and for the Public Health System of Rio Grande do Sul". This step aimed to characterize the use of the judicial process in order to obtain treatment of PKU in the state of Rio Grande do Sul (RS). Methodology: A retrospective, observational study, based on analysis of court cases of individuals with PKU that entered with judicial lawsuits between 2001 and 2010 requesting some form of treatment for this disease in RS. Data corresponding to the period between filing the lawsuit and court ruling were analyzed. Results: We identified 20 cases filed in the period that met the inclusion criteria, in which full access to the documents for analysis was only possible in 19 cases. Only 2/19 processes aimed at obtaining therapies different from the metabolic formula. In 17/19 cases it was reported that there was prior request of treatment granted by the Department of Health of the state of RS. Figured as defendants the state of RS (n=19), the Union (n=1), and municipalities (n=4). Applications for advance relief were granted in all cases. At the end of the analysis, 18/19 cases had court ruling, obliging that the defendants provide the required inputs. Conclusions: The data suggest a violation of the right to health and interruption of treatment supplied by the State as the main reasons for the use of the judicial process. There is also evidence that problems, such as management of medications and lengthy procurement processes, contribute to the judicialization of PKU in the state of RS. Contrary to what happens with other genetic diseases, in the case of PKU, the quest via litigation aims to obtain a product that is already included in the national pharmaceutical assistance policy, a finding that suggests that management failures are one of the factors triggering judicialization in the country.

A Fenilcetonúria (PKU) é uma doença genética rara detectada pelo Programa Nacional de Triagem Neonatal (PNTN) por meio do "teste do pezinho". Uma vez diagnosticada e tratada precocemente com dieta específica e fórmula metabólica isenta de fenilalanina (Phe), a ocorrência de retardo mental é prevenida nestes pacientes. Mesmo sendo fornecida gratuitamente pelo Sistema Único de Saúde (SUS), mediante protocolo clínico, estima-se que os pacientes com PKU têm encontrado dificuldades de acesso à fórmula metabólica, recorrendo à via judicial para garantir a continuidade de seu tratamento. Não existem estudos sobre os fatores que levam os pacientes com PKU a ingressarem na justiça em busca do acesso ao seu tratamento, tampouco que caracterizem os argumentos utilizados pelos poderes públicos na tentativa de resolução desses conflitos. Objetivos: Este estudo constitui-se em uma das etapas de um projeto mais amplo intitulado "Acesso e Adesão ao Tratamento da Fenilcetonúria: avaliação da judicialização e do impacto médico e socioeconômico para os pacientes e sua famílias, e para o Sistema Único de Saúde do Rio Grande do Sul". Esta etapa teve por objetivo caracterizar o uso da via judicial para a obtenção do tratamento da PKU no Estado do Rio Grande do Sul (RS). Metodologia: estudo observacional e retrospectivo, baseado na análise de processos judiciais de indivíduos com PKU que ingressaram na justiça entre 2001 e 2010 e que solicitaram alguma forma de tratamento para essa doença. Foram analisados os dados correspondentes ao período compreendido entre a propositura da ação e a sentença. Resultados: foram identificados 20 processos ajuizados no período analisado, e que preenchiam os critérios de inclusão, sendo que o acesso integral aos documentos para análise só foi possível em 19 casos. Apenas 2/19 dos processos visavam à obtenção de terapias diferentes da fórmula metabólica. Em 17/19 dos processos havia relato de solicitação prévia de fornecimento do tratamento deferida pela Secretaria de Saúde – RS. Figuraram como réus o estado do RS (n=19), a União (n=1) e municípios (n=4). Os pedidos de antecipação de tutela foram deferidos em todos os processos. Ao final das análises, 18/19 dos processos possuíam sentenças, obrigando os réus a fornecerem os insumos solicitados. Conclusões: os dados sugerem a violação do direito à saúde e a interrupção do fornecimento do tratamento pelo Estado como as principais razões para o uso da via judicial. Há evidências ainda, de que problemas como gestão de estoque e processos licitatórios morosos contribuam para a judicialização da PKU no RS. Ao contrário do que acontece com outras doenças genéticas, no caso da PKU a busca pela via judicial visa à obtenção de um produto que já está incluído na política de assistência farmacêutica nacional, achado que sugere que falhas de gestão são um dos fatores desencadeantes da judicialização no país. / Phenylketonuria (PKU) is a rare genetic disease detected by the Brazilian National Neonatal Screening Program (PNTN) through the "heel-stick test". Once diagnosed and treated early with a specific diet and metabolic phenylalanine-free formula (Phe), the occurrence of mental retardation is prevented in these patients. Even being provided free of charge by the Public Health System through National Guidelines, it is estimated that patients with PKU have found difficulty in obtaining the metabolic formula, resorting to the courts to ensure the continuity of their treatment. There are no studies on the factors that lead patients with PKU to file lawsuits in search of justice to have access to their treatment, nor that characterize the arguments used by the government in an attempt to solve these conflicts. Objectives: This study constitutes one of the steps of a broader project entitled "Access and Adherence to Phenylketonuria Treatment: evaluation of judicialization and the medical and socio-economic impact for patients and their families, and for the Public Health System of Rio Grande do Sul". This step aimed to characterize the use of the judicial process in order to obtain treatment of PKU in the state of Rio Grande do Sul (RS). Methodology: A retrospective, observational study, based on analysis of court cases of individuals with PKU that entered with judicial lawsuits between 2001 and 2010 requesting some form of treatment for this disease in RS. Data corresponding to the period between filing the lawsuit and court ruling were analyzed. Results: We identified 20 cases filed in the period that met the inclusion criteria, in which full access to the documents for analysis was only possible in 19 cases. Only 2/19 processes aimed at obtaining therapies different from the metabolic formula. In 17/19 cases it was reported that there was prior request of treatment granted by the Department of Health of the state of RS. Figured as defendants the state of RS (n=19), the Union (n=1), and municipalities (n=4). Applications for advance relief were granted in all cases. At the end of the analysis, 18/19 cases had court ruling, obliging that the defendants provide the required inputs. Conclusions: The data suggest a violation of the right to health and interruption of treatment supplied by the State as the main reasons for the use of the judicial process. There is also evidence that problems, such as management of medications and lengthy procurement processes, contribute to the judicialization of PKU in the state of RS. Contrary to what happens with other genetic diseases, in the case of PKU, the quest via litigation aims to obtain a product that is already included in the national pharmaceutical assistance policy, a finding that suggests that management failures are one of the factors triggering judicialization in the country.

A Fenilcetonúria (PKU) é uma doença genética rara detectada pelo Programa Nacional de Triagem Neonatal (PNTN) por meio do "teste do pezinho". Uma vez diagnosticada e tratada precocemente com dieta específica e fórmula metabólica isenta de fenilalanina (Phe), a ocorrência de retardo mental é prevenida nestes pacientes. Mesmo sendo fornecida gratuitamente pelo Sistema Único de Saúde (SUS), mediante protocolo clínico, estima-se que os pacientes com PKU têm encontrado dificuldades de acesso à fórmula metabólica, recorrendo à via judicial para garantir a continuidade de seu tratamento. Não existem estudos sobre os fatores que levam os pacientes com PKU a ingressarem na justiça em busca do acesso ao seu tratamento, tampouco que caracterizem os argumentos utilizados pelos poderes públicos na tentativa de resolução desses conflitos. Objetivos: Este estudo constitui-se em uma das etapas de um projeto mais amplo intitulado "Acesso e Adesão ao Tratamento da Fenilcetonúria: avaliação da judicialização e do impacto médico e socioeconômico para os pacientes e sua famílias, e para o Sistema Único de Saúde do Rio Grande do Sul". Esta etapa teve por objetivo caracterizar o uso da via judicial para a obtenção do tratamento da PKU no Estado do Rio Grande do Sul (RS). Metodologia: estudo observacional e retrospectivo, baseado na análise de processos judiciais de indivíduos com PKU que ingressaram na justiça entre 2001 e 2010 e que solicitaram alguma forma de tratamento para essa doença. Foram analisados os dados correspondentes ao período compreendido entre a propositura da ação e a sentença. Resultados: foram identificados 20 processos ajuizados no período analisado, e que preenchiam os critérios de inclusão, sendo que o acesso integral aos documentos para análise só foi possível em 19 casos. Apenas 2/19 dos processos visavam à obtenção de terapias diferentes da fórmula metabólica. Em 17/19 dos processos havia relato de solicitação prévia de fornecimento do tratamento deferida pela Secretaria de Saúde – RS. Figuraram como réus o estado do RS (n=19), a União (n=1) e municípios (n=4). Os pedidos de antecipação de tutela foram deferidos em todos os processos. Ao final das análises, 18/19 dos processos possuíam sentenças, obrigando os réus a fornecerem os insumos solicitados. Conclusões: os dados sugerem a violação do direito à saúde e a interrupção do fornecimento do tratamento pelo Estado como as principais razões para o uso da via judicial. Há evidências ainda, de que problemas como gestão de estoque e processos licitatórios morosos contribuam para a judicialização da PKU no RS. Ao contrário do que acontece com outras doenças genéticas, no caso da PKU a busca pela via judicial visa à obtenção de um produto que já está incluído na política de assistência farmacêutica nacional, achado que sugere que falhas de gestão são um dos fatores desencadeantes da judicialização no país. / Phenylketonuria (PKU) is a rare genetic disease detected by the Brazilian National Neonatal Screening Program (PNTN) through the "heel-stick test". Once diagnosed and treated early with a specific diet and metabolic phenylalanine-free formula (Phe), the occurrence of mental retardation is prevented in these patients. Even being provided free of charge by the Public Health System through National Guidelines, it is estimated that patients with PKU have found difficulty in obtaining the metabolic formula, resorting to the courts to ensure the continuity of their treatment. There are no studies on the factors that lead patients with PKU to file lawsuits in search of justice to have access to their treatment, nor that characterize the arguments used by the government in an attempt to solve these conflicts. Objectives: This study constitutes one of the steps of a broader project entitled "Access and Adherence to Phenylketonuria Treatment: evaluation of judicialization and the medical and socio-economic impact for patients and their families, and for the Public Health System of Rio Grande do Sul". This step aimed to characterize the use of the judicial process in order to obtain treatment of PKU in the state of Rio Grande do Sul (RS). Methodology: A retrospective, observational study, based on analysis of court cases of individuals with PKU that entered with judicial lawsuits between 2001 and 2010 requesting some form of treatment for this disease in RS. Data corresponding to the period between filing the lawsuit and court ruling were analyzed. Results: We identified 20 cases filed in the period that met the inclusion criteria, in which full access to the documents for analysis was only possible in 19 cases. Only 2/19 processes aimed at obtaining therapies different from the metabolic formula. In 17/19 cases it was reported that there was prior request of treatment granted by the Department of Health of the state of RS. Figured as defendants the state of RS (n=19), the Union (n=1), and municipalities (n=4). Applications for advance relief were granted in all cases. At the end of the analysis, 18/19 cases had court ruling, obliging that the defendants provide the required inputs. Conclusions: The data suggest a violation of the right to health and interruption of treatment supplied by the State as the main reasons for the use of the judicial process. There is also evidence that problems, such as management of medications and lengthy procurement processes, contribute to the judicialization of PKU in the state of RS. Contrary to what happens with other genetic diseases, in the case of PKU, the quest via litigation aims to obtain a product that is already included in the national pharmaceutical assistance policy, a finding that suggests that management failures are one of the factors triggering judicialization in the country.

Orientador: Carmen Silvia Bertuzzo / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-11T19:43:52Z (GMT). No. of bitstreams: 1 Pollice_ErikaLourenco_D.pdf: 2177498 bytes, checksum: 0cac25634d3fc74eb0d114647ac766a7 (MD5) Previous issue date: 2008 / Resumo: A fenilcetonúria (PKU) é uma doença autossômica recessiva que na sua forma clássica é causada pela deficiência da enzima hidroxilase da fenilalanina (PAH), cuja função é catalisar a reação de hidroxilação da fenilalanina em tirosina. Uma alteração no gene da PAH leva a deficiência de hidroxilase da fenilalanina. O diagnóstico precoce é de suma importância, uma vez, que se não tratada, pode ocasionar retardo mental. A dieta pobre em fenilalanina previne esse retardo, tornando o diagnóstico precoce fundamental. Mais de 500 mutações que causam algum grau de hiperfenilalaninemia foram descritas no gene PAH. O conjunto e freqüências das mutações variam conforme a população. A população brasileira apresenta mistura étnica complexa, a freqüência das mutações varia muito conforme a região estudada. No Brasil, foram estudadas amostras de São Paulo (SP) e Rio Grande do Sul (RS) e Minas Gerais (MG). A grande variação observada nos níveis de fenilalanina nos primeiros meses de vida e sua correlação diminuída com o diagnóstico aponta para o seu valor prognóstico baixo, reforçando a necessidade da triagem de mutações. Este estudo teve como objetivo investigar as mutações mais freqüentes e estabelecer o perfil gênico de pacientes com PKU diagnosticados em serviços de triagem neonatal e que estejam em acompanhamento no Serviço Regional de Triagem Neonatal da UNICAMP. Foram analisadas as mutações V388M, IVS10nt11, IVS12nt1, R408W, através da técnica de PCR e digestão com enzima de restrição específica. Nos casos onde não foi detectada nenhuma dessas mutações, foi realizada a técnica de DHPLC com posterior sequenciamento dos pacientes com padrão de eluição alterado. As mutações R408W, IVS10-11G?A, IVS12+1G?A e V388M, não foram encontradas com grande freqüência em nossa amostra de fenilcetonúricos da região de Campinas. As demais mutações identificadas foram bem variadas. Os pacientes analisados neste trabalho possuem um perfil gênico distinto de indivíduos pertencentes a outras regiões do Brasil e relatados na literatura, refletindo na grande miscigenação existente na população brasileira / Abstract: Phenylketonuria (PKU) is an autosomal recessive genetic disorder caused by deficiency of the hepatic phenylalanine-4-hydroxylase (PAH), which catalyzes hydroxylation of phenylalanine to tyrosine. Deficiency of PAH is caused by mutations in the PAH gene, resulting in high serum levels of phenylalanine and mental retardation. Restriction of phenylalanine intake prevents neurological impairments of PKU. Mutation screening of PAH gene is a very useful strategy for accurate diagnosis, newborn phenotype prediction and to implement a dietary without phenylalanine. To date, almost 500 mutations have been identified in the PAH gene. The PAH mutation frequency could change with the studied population. The Brazilian population is compound by a great ethnic variation and the PAH mutation frequency could be very different depending on witch Brazilian region was studied. Previous studies in Brazilian patients were performed at São Paulo (SP), Rio Grande do Sul (RS) and Minas Gerais (MG) and the mutation frequency can be changed according to the population studied. The aim of this work was to analyze the most frequent PAH mutations previously described in other populations and determine the PKU molecular characterization in patients identified in the neonatal service of the Regional Newborn Screening Service/Campinas. The V388M, IVS10nt11, IVS12nt1 and R408W mutations were analyzed by PCR and RFLP. In addition, DHPLC and automatic sequencing were performed for patients whose initial screening was negative. Any of the R408W, IVS10-11G?A, IVS12+1G?A and V388M mutations was found in great frequency in our sample from Campinas region. The other mutations that could be detected in this sample were diversified. The genetic characteristics in these patients were different than others Brazilian populations / Doutorado / Ciencias Biomedicas / Doutor em Ciências Médicas

Background Tetrahydrobiopterin (BH4)-sensitive phenylketonuria (PKU) can be treated with sapropterin dihydrochloride. We studied metabolic control and health-related quality of life (HRQoL) in PKU patients treated with BH4. Subjects and methods Based on the review of neonatal BH4 test results and mutation analysis in 41 PKU patients, 19 were identified as potentially BH4-sensitive (9 females, 10 males, age 4–18 years). We analyzed phenylalanine (phe) concentrations in dried blood samples, nutrition protocols, and HRQoL questionnaires (KINDL®) beginning from 1 year before, during the first 42 days, and after 3 months of BH4 therapy. Results Eight BH4-sensitive patients increased their phe tolerance (629±476 vs. 2131±1084 mg, p00.006) while maintaining good metabolic control (phe concentration in dried blood 283±145 vs. 304±136 μM, p01.0). Six of them were able to stop dietary protein restriction entirely. BH4- sensitive patients had average HRQoL scores that were comparable to age-matched healthy children. There was no improvement in HRQoL scores after replacing classic dietary treatment with BH4 supply, although personal reports given by the patients and their parents suggest that available questionnaires are inappropriate to detect aspects relevant to inborn metabolic disorders. Discussion BH4 can allow PKU patients to increase their phe consumption significantly or even stop dietary protein restrictions. Unexpectedly, this does not improve HRQoL as assessed with KINDL®, partly due to high scores even before BH4 therapy. Specific questionnaires should be developed for inborn metabolic disorders.

O presente trabalho teve como objetivo estimar a concentração de Phe em 22 amostras de sopas desidratadas instantâneas, por serem úteis na diversificação do cardápio de fenilcetonúricos. Foi analisada a concentração de glutamato monossódico (GMS) por ser uma provável fonte de N não protéico (NNP) que pode resultar em concentrações protéicas superestimadas. A concentração de proteína real estimada foi realizada após precipitação da proteína com TCA 10%, seguida da análise do N pelo método de Kjeldahl, o qual foi convertido para proteína por um fator de conversão (Fc) adequado. A legislação Brasileira estabelece um Fc de 5,75 para proteínas vegetais, 6,25 para proteínas da carne e misturas de proteínas e 6,38 para proteínas lácteas. A concentração de GMS foi determinada por método enzimático com eletrodo sensível a amônia. A concentração de proteína bruta (N totalxFc) variou entre 6,05 e 21,51%, tendo sido estes valores, na maioria das vezes, similares aos declarados no rótulo, indicando que os fabricantes utilizam o N totalxFc para expressar o conteúdo protéico. A concentração protéica real estimada foi baixa, variando entre 1,28 e 16,31%. A concentração de NNP teve uma variação de 0,33 a 1,27g/100g de amostra, representando de 11,10 a 81,33% do NT presente. A concentração de GMS variou entre 1,01 e 7,86g/100g de amostra, sendo que o N proveniente deste realçador de sabor contribuiu com 2,53 a 47,71% na quantidade total de N. A diferença entre a concentração de proteína bruta e real estimada se deve à presença de NNP, na forma de GMS. Com base nos valores protéicos reais estimados, foram calculados os teores de Phe que variaram entre 51,16 e 652,24mg de Phe/100g de amostra. Assim, recomenda-se que todos os alimentos adicionados de realçadores de sabor sejam analisados quanto à concentração de proteína real para que a Phe seja corretamente estimada. / The aim of this work was to estimate the concentration of Phe in 22 samples of commercially available dehydrated soups, as they are useful to add variety to the diet for phenilketonurics. The monosodium glutamate (MSG) contents had been analyzed as it is a likely source of non protein N (NPN) that might result in overestimated protein contents. The true protein content was accomplished after protein precipitation with 10% TCA and followed by N analysis according to the Kjeldahl method, which was converted to protein by a suitable conversion factor (Fc). The Brazilian legislation establishes a Fc of 5,75 for vegetables proteins, 6,25 for meat and blended proteins and 6,38 for milk proteins. The MSG concentration was determined by an enzymatic method employing an ammonia gas-sensitive electrode. The crude protein content (total NxFc) varied from 6,05 to 21,51% and were similar, in most cases, to those stated on the label, showing that manufacturers use total NxFc to express the protein content. Nevertheless, the true protein content was low, varying from 1,28 to 16,31%. The NPN concentration varied from 0,33 to 1,27g/100g of sample, which represents from 11,10 to 81,33% of the existing total N. The MSG concentration varied from 1,01 to 7,86g/100g of sample; the N arose from this flavor enhancer gives about 2,53 to 47,71% of the total quantity of N. The difference between the crude protein and true protein contents is due to the presence of MSG-like NPN. The Phe concentrations were calculated in accordance with the true protein values and varied from 51,16 to 652,24 mg/100g of sample. Thus, we recommend the analysis of all flavor-enhancer-added foods, in order to get reliable results for Phe estimation from the protein contents.

A fenilcetonúria (PKU) é caracterizada por uma deficiente atividade da fenilalanina hidroxilase (PAH), que converte fenilalanina em tirosina. Consequentemente, pacientes fenilcetonúricos apresentam níveis aumentados de fenilalanina no sangue e em tecidos. A fenilalanina atinge níveis tóxicos no cérebro e, assim, pode levar a deficiência intelectual grave se não tratada. Hoje em dia, os pacientes fenilcetonúricos são diagnosticados através de programas de triagem neonatal e são colocados em tratamento imediatamente. O tratamento da PKU é baseado em uma dieta restrita em fenilalanina juntamente com uma mistura de aminoácidos, que visa reduzir a ingestão de fenilalanina ao mesmo tempo em que fornece todos os outros aminoácidos e nutrientes essenciais. Apesar de eficiente, o tratamento é extremamente difícil de seguir e, portanto, os pacientes ainda apresentam altos níveis de fenilalanina e seus problemas associados, tais como estresse oxidativo, distúrbios motores e cognitivos. Ainda, a dieta em si é tão restritiva que a completa adesão pode levar a problemas nutricionais como obesidade e perturbações hormonais. A fim de abordar estas questões na PKU, é necessário compreender os mecanismos pelos quais a fenilalanina perturba homeostasia, bem como propor novas estratégias de tratamento para a doença. Portanto, esta tese teve como objetivo verificar o estado metabólico basal e em exercício aeróbico em pacientes fenilcetonúricos, além de avaliar possíveis benefícios do treinamento físico em camundongos PAHenu2. Para tanto, foram avaliados composição basal, estado nutricional, taxa metabólica basal, bem como a resposta ventilatória e bioquímica a uma sessão de exercício aeróbico em pacientes fenilcetonúricos em comparação com controles pareados, por bioimpedância elétrica e calorimetria indireta, respectivamente. Foram encontrados resultados similares entre pacientes e controles para todos os marcadores antropométricos e nutricionais, mostrando, assim, que os pacientes fenilcetonúricos têm a mesma composição corporal e perfil metabólico que controles. Além disso, os níveis de fenilalanina não se modificaram imediatamente após o exercício em comparação com a condição de repouso, demonstrando assim que o exercício aeróbico é seguro para pacientes fenilcetonúricos. No modelo animal de PKU, este estudo avaliou os efeitos crônicos do exercício aeróbico voluntário no cérebro de camundongos PAHenu2. Apesar de correrem menores distâncias do que os controles, os camundongos PKU apresentaram melhoras em parâmetros de estresse oxidativo no cérebro, embora os níveis de fenilalanina no sangue e no cérebro permanecessem inalterados. Os animais PKU apresentaram habilidades motoras e de equilíbrio deficientes em comparação com os controles, enquanto o exercício não afetou esses parâmetros comportamentais. Adicionalmente, os aminoácidos gliconeogênicos e os relacionados com o ciclo da ureia foram encontrados em níveis inferiores no plasma dos animais PKU que se exercitaram em comparação com os sedentários. Por outro lado, os camundongos selvagens não apresentaram nenhuma alteração causada pelo exercício. Assim, os fenilcetonúricos não apresentam distúrbios em marcadores metabólicos tanto em repouso como durante exercício aeróbico. Por conseguinte, os fenilcetonúricos devem ser encorajados a praticar exercício para, possivelmente, beneficiarem-se das adaptações positivas geradas pelo treinamento físico. No entanto, o pequeno número de pacientes avaliados em nossos estudos destaca a necessidade de mais pesquisas para descrever o exercício mais adequado para pacientes com PKU. / Phenylketonuria (PKU) is characterized by poor phenylalanine hydroxylase (PAH) activity, which acts converting phenylalanine into tyrosine. Consequently, PKU patients show increased levels of phenylalanine in the blood and tissues. Phenylalanine reaches toxic levels in the brain and therefore can lead to severe mental retardation, if untreated. Nowadays, PKU patients are diagnosed through newborn screening programs and are put on treatment immediately. PKU treatment is based on a phenylalanine-restricted diet along with an amino acid mixture, which aims to reduce the intake of phenylalanine while providing other essential amino acids and nutrients. Despite efficient, the treatment is extremely hard to follow so that PKU patients show high levels of phenylalanine and related issues such as oxidative stress, motor and cognitive disturbances. Moreover, the diet itself is so restrictive that adhering to it may lead to nutritional problems like obesity and hormonal disruptions. In order to tackle these issues in PKU, it is necessary to understand the mechanisms in which phenylalanine disturbs homeostasis as well as propose new treatment strategies for the disease. Therefore, this thesis aimed to evaluate metabolic markers in rest and exercise in PKU patients, as well as to verify the possible benefits of exercise in the brain of PAHenu2 mice. For that, we evaluated basal body composition, nutritional status, basal metabolic rate, as well as ventilatory and biochemical response to an aerobic exercise session in PKU patients and matched-controls using electrical bioimpedance analysis and indirect calorimetry, respectively. The groups did not differ for anthropometric and nutritional markers, thus showing that PKU patients have the same body and metabolic profiles as controls. Moreover, phenylalanine levels were not modified immediately after exercise in comparison to rest condition, thus proving that aerobic exercise is safe for PKU patients. In the animal model of PKU, we evaluated the effects of voluntary training in the brain of PAHenu2 mice. Despite running less distances than the controls, the PKU mice showed improved oxidative stress parameters although phenylalanine levels in the blood and in brain remained unchanged. PKU animals showed poor motor and balance skills than controls while exercise did not affect these behavioral markers. In addition, gluconeogenic and urea cycle-related amino acids were found in lower levels in the plasma of the exercised PKU animals in comparison to the sedentary PKU group. On the other hand, wild-type mice did not show any of those changes. Taken together, we conclude that PKU patients do not show disturbed metabolism in rest and during aerobic exercise. Therefore, PKU patients have to be encouraged to exercise in order to possibly benefit from long-term exercise-related adaptations. Nevertheless, the small number of patients evaluated in our studies highlights the need of further research to describe the most suitable exercise for PKU patients.

En raison du risque de perturbation des fonctions exécutives (FE), les recommandations médicales préconisent un suivi systématique du développement neuropsychologique des enfants atteints de phénylcétonurie, diagnostiqués et traités précocement (PCU-TP). En revanche, des divergences existent quant aux modalités pratiques d’évaluation. Ce travail de thèse a pour objectif d’interroger la pertinence de différents outils d’évaluation des FE en regard de la compréhension du phénotype neuropsychologique de ces enfants. Il s’agit d’apporter des préconisations d'évaluation puis de les confronter aux recommandations actuellement en vigueur. Dans ce contexte, 31 enfants PCU-TP ont été évalués à l’aide de tâches exécutives basées sur la performance et d’un questionnaire évaluant les comportements exécutifs à la maison et à l'école. Les résultats confirment la présence de difficultés exécutives par rapport à des enfants contrôles. Les difficultés décrites par l'entourage semblent majorées en regard des troubles observés aux tâches, suggérant que ces deux types d’outil évaluent des aspects exécutifs différents. Ce travail incite à préconiser l’utilisation d’outils variés et complémentaires et justifie la pertinence d’une évaluation plurielle et exhaustive des différentes composantes exécutives.Reste le problème majeur des outils actuellement disponibles. Dans cette perspective, la dynamique pluridisciplinaire associant cliniciens et universitaires est à encourager afin de proposer des outils fiables, permettant une évaluation puis une prise en charge au plus près des difficultés des patients. / Due to the risk of the impairment of Executive functions (EF), medical recommendations advocate asystematic follow up of the neuropsychological development for children with early and continuously treated phenylketonuria (ECT-PKU). However, there are discrepancies in the practical modalities of evaluation.This thesis is looking to question the relevance of the different evaluation tools for the EF with regards to the understanding of these children’s neuropsychological phenotype. It is about bringing evaluation recommendations and comparing them with the current guidelines. In this context, thirty one children with ECTPKU have been evaluated with executive tasks based on performance, and with a questionnaire assessing everyday executive functioning at home and at school.The results confirm some executive difficulties compared to control children. The difficulties described by the parents and teachers seem to be increased in relation to the disorders observed during the tasks. This suggests that these two types of tools evaluate different executive aspects. This work recommends the use of varied and complementary tools and it justifies the relevance of a plural and exhaustive evaluation of the different executive components. The major issue of the tools currently available remains. In this perspective, the pluridisciplinary dynamic associating clinicians and scholars is to be encouraged in order to offer reliable tools and thus allowing an evaluation, and a care and support, that are closer and more appropriate to the patient's difficulties.