Análise da densidade mineral óssea em pacientes com fenilcetonúria e sua correlação com parâmetros nutricionais / Bone mineral density assessment in patients with phenylketonuria and its correlation with nutritional parameters

Introdução: Redução da densidade mineral óssea (DMO) está associada à Fenilcetonúria (PKU), mas a causa desta associação não é completamente entendida. O objetivo desse estudo foi avaliar a ingestão de nutrientes relacionados ao metabolismo ósseo (cálcio, fósforo, magnésio, potássio), e sua associação com a DMO em pacientes com PKU. Métodos: Estudo transversal, observacional. Foram incluídos 15 pacientes (PKU Clássica=8; Leve=7; mediana de idade=16 anos, IQ=15-20), todos em tratamento com dieta restrita em fenilalanina (Phe) e 13 em uso de fórmula metabólica. Foi realizado recordatório alimentar de 24 horas de um dia e demais dados (histórico de fraturas, parâmetros antropométricos, DMO e níveis plasmáticos de Phe, Tyr, cálcio) foram obtidos por revisão de prontuário. Resultados: Nenhum paciente apresentou histórico de fraturas e seis realizavam suplementação de cálcio (alteração prévia da DMO=5; baixa ingestão=1). A mediana dos níveis de Phe foi 11,6 mg/dL (IQ=9,3-13,3). Em relação ao recordatório alimentar, dez indivíduos apresentaram inadequado consumo de carboidratos; 14, de lipídeos; 9, de cálcio; 11, de magnésio; 13, de fósforo; e todos de potássio. A mediana da DMO foi de 0,989 g/cm2 (IQ=0,903-1,069), sendo duas classificadas como reduzidas para idade, ambas de pacientes com PKU Leve que recebiam suplementação de cálcio. Não foi observada correlação entre níveis de Phe, DMO e demais variáveis analisadas. Conclusão: Redução da DMO não foi frequente na amostra, embora ingestão inadequada de cálcio assim o seja. Estudos adicionais são necessários para esclarecer o efeito da Phe e da ingestão dietética sobre o metabolismo ósseo na PKU. (AU)

Introduction: Reduced bone mineral density (BMD) is associated with phenylketonuria (PKU), but this association is not completely understood. This research aimed to evaluate intake of nutrients related to bone metabolism (calcium, phosphorus, magnesium, potassium) and its association with BMD in patients with PKU. Methods: In this cross-sectional, observational study, 15 patients with PKU (Classical=8, Mild=7; median age=16 years, IQ=15-20 years) were included, all of them on phenylalanine (Phe) restricted diet and 13 being supplemented with a metabolic formula. A 24-hour dietary recall was performed and remaining data (history of fractures, anthropometric parameters, BMD and plasma Phe, tyrosine and calcium levels) were obtained through medical chart review. Results: No patient had any fractures and six received calcium supplements, five due to previous change in BMD and one due to inadequate nutritional intake. Median Phe level was 11.6 mg/dL (IQ=9.3-13.3). In relation to dietary recall, all individuals had inadequate intake of some nutrient (carbohydrate=10; lipids=14; calcium=9; magnesium=11; phosphorus=13; potassium=15). The median BMD was 0.989 g/cm2 (IQ=0.903-1.069). Two cases were classified as low BMD for age, both in patients with mild PKU receiving calcium supplements. Conclusion: Reduced BMD was not common in this sample, although inadequate calcium intake was frequently reported. Additional studies are needed to clarify the effect of Phe and dietary intake on bone metabolism in patients with PKU.(AU)

Assessment of newborn screening in the public health system of a municipality in northern Rio Grande do Sul

Introduction: Newborn screening allows the screening of diseases that are still in the asymptomatic period and whose early diagnosis and treatment are associated with reduced infant morbidity and mortality. The aim of this study was to evaluate the public National Newborn Screening Program in the municipality of Carazinho, state of Rio Grande do Sul (RS), Brazil. Methods: This was a population-based, retrospective, descriptive study. We collected and transcribed data from a database of the Carazinho municipal laboratory, which is affiliated with the referral center for newborn screening in RS. The records of all individuals undergoing newborn screening from 2005 to 2010 were reviewed, and information was collected on the program coverage, time elapsed between birth and screening (first collection), and test results. Results: The program had a coverage of 75.5%. One suspected case of phenylketonuria, three suspected cases of congenital hypothyroidism and no suspected cases of hemoglobinopathy were identified. In addition, there were 18 positive results for hemoglobin S heterozygosity, five for hemoglobin D heterozygosity, two for hemoglobin C heterozygosity, and one for a rare variant hemoglobin. When analyzing the newborn's age at the time of blood collection, it was observed that 63.1% were within the recommended age range. Conclusions: Our findings suggest the need for optimization of public newborn screening in the evaluated municipality. The strategies to be adopted should include education of the population and especially of managers and health professionals about the importance of newborn screening. (AU)

Nutritional Status and Body Composition in Patients With Hepatic Glycogen Storage Diseases Treated With Uncooked Cornstarch—A Controlled Study

Abstract Hepatic glycogen storage diseases (GSDs) are genetic diseases associated with fasting hypoglycemia. Periodic intake of uncooked cornstarch is one of the treatment strategies available for those disorders. For reasons that are still not clear, patients with hepatic GSDs may be overweight. Aims: To assess nutritional status and body composition in patients with hepatic GSDs receiving uncooked cornstarch. Methods: The sample included 25 patients with hepatic GSD (type Ia = 14; Ib = 6; III = 3; IX? = 1; IX? = 1), with a median age of 11.0 years (interquartile range [IQR] = 9.0-17.5), matched by age and gender with 25 healthy controls (median age = 12.0 years, IQR = 10.0-17.5). Clinical, biochemical, and treatment-related variables were obtained from medical records. Nutritional status and body composition were prospectively evaluated by bioelectrical impedance. Results: Patients and controls did not differ with regard to age and gender. Height was significantly reduced in patients (median = 1.43 m, IQR = 1.25-1.54) in comparison to controls (median = 1.54 m, IQR = 1.42-1.61; P = .04). Body mass index for age z-score and fat mass percentage were higher in patients (median = 1.84, IQR = 0.55-3.06; and 27.5%, IQR = 22.6-32.0, respectively) than in controls (median = 0.86, IQR = ?0.55 to 1.82; P = .04 and 21.1%, IQR = 13.0-28.3; P = .01, respectively). When patients were stratified by type, those with GSD Ia had significantly higher adiposity (median fat mass = 28.7%, IQR = 25.3-32.9) than those with GSD III and GSD IX?/? (median fat mass = 20.9%, IQR = 14.9-22.6; P = .02). Conclusions: Our findings suggest that patients with hepatic GSD on treatment with cornstarch, especially those with GSD Ia, exhibit abnormalities in nutritional status and body composition, such as short stature and a trend toward overweight and obesity.

Maple syrup urine disease in Brazil: a panorama of the last two decades / Doença da urina de xarope de bordo no Brasil: um panorama das últimas duas décadas

OBJECTIVE: To characterize a sample of Brazilian patients with maple syrup urine disease (MSUD) diagnosed between 1992 and 2011. METHODS: In this retrospective study, patients were identified through a national reference laboratory for the diagnosis of MSUD and through contact with other medical genetics services across Brazil. Data were collected by means of a chart review. RESULTS: Eighty-three patients from 75 families were enrolled in the study (median age, 3 years; interquartile range [IQR], 0.57-7). Median age at onset of symptoms was 10 days (IQR 5-30), whereas median age at diagnosis was 60 days (IQR 29-240, p = 0.001). Only three (3.6%) patients were diagnosed before the onset of clinical manifestations. A comparison between patients with (n = 12) and without (n = 71) an early diagnosis shows that early diagnosis is associated with the presence of positive family history and decreased prevalence of clinical manifestations at the time of diagnosis, but not with a better outcome. Overall, 98.8% of patients have some psychomotor or neurodevelopmental delay. CONCLUSION: In Brazil, patients with MSUD are usually diagnosed late and exhibit neurological involvement and poor survival even with early diagnosis. We suggest that specific public policies for diagnosis and treatment of MSUD should be developed and implemented in the country. .

OBJETIVO: Caracterizar uma amostra de pacientes brasileiros com a doença da urina de xarope de bordo (DXB) diagnosticados entre 1992 e 2011. MÉTODOS: Os pacientes foram identificados por meio de um laboratório de referência nacional para o diagnóstico de DXB e por meio do contato com outros serviços de genética médica no Brasil. Os dados foram coletados por meio de uma revisão de prontuários. RESULTADOS: Foram incluídos no estudo 83 pacientes de 75 famílias (idade média: três anos; intervalo interquartil (IQR): 0,57-7). A idade média no surgimento dos sintomas era de 10 dias (IQR: 5-30), ao passo que a idade média no diagnóstico era de 60 dias (IQR: 29-240; p = 0,001). Somente três (3,6%) pacientes foram diagnosticados antes do surgimento de manifestações clínicas. Uma comparação entre pacientes com (n = 12) e sem (n = 71) um diagnóstico precoce mostra que o diagnóstico precoce está associado à presença de histórico familiar positivo e à redução na prevalência de manifestações clínicas no momento do diagnóstico, porém sem melhor resultado. Em geral, 98,8% dos pacientes têm algum atraso no desenvolvimento psicomotor ou neurológico. CONCLUSÃO: No Brasil, os pacientes com DXB normalmente recebem um diagnóstico tardio e exibem um envolvimento neurológico e baixa sobrevivência, mesmo com um diagnóstico precoce. Sugerimos que políticas públicas específicas para o diagnóstico e tratamento da DXB sejam desenvolvidas e implementadas no país. .

Access to treatment for phenylketonuria by judicial means in Rio Grande do Sul, Brazil / Acesso ao tratamento para fenilcetonúria por via judicial no Rio Grande do Sul, Brasil

Treatment of phenylketonuria (PKU) includes the use of a metabolic formula which should be provided free of charge by the Unified Health System (SUS). This retrospective, observational study sought to characterize judicial channels to obtain PKU treatment in Rio Grande do Sul (RS), Brazil. Lawsuits filed between 2001- 2010 and having as beneficiaries PKU patients requesting treatment for the disease were included. Of 20 lawsuits filed, corresponding to 16.8% of RS patients with PKU, 19 were retrieved for analysis. Of these, only two sought to obtain therapies other than metabolic formula. In all the other 17 cases, prior treatment requests had been granted by the State Department of Health. Defendants included the State (n = 19), the Union (n = 1), and municipalities (n = 4). In 18/19 cases, the courts ruled in favor of the plaintiffs. Violation of the right to health and discontinuation of State-provided treatment were the main reasons for judicial recourse. Unlike other genetic diseases, patients with PKU seek legal remedy to obtain a product already covered by the national pharmaceutical assistance policy, suggesting that management failures are a driving factor for judicialization in Brazil.

O tratamento da fenilcetonúria (PKU) inclui o uso de uma fórmula metabólica (FM) fornecida sem custos pelo Sistema Único de Saúde (SUS). O objetivo do estudo foi caracterizar o uso da via judicial para obter tratamento para PKU no estado do Rio Grande do Sul (RS), Brasil, através de um estudo retrospectivo e observacional, analisando ações judiciais. Foram incluídas ações judiciais arquivadas entre 2001-2010 que possuíam como beneficiários indivíduos com PKU solicitando alguma forma de tratamento para PKU. Foram localizados 20 casos, correspondendo a 16,8% dos pacientes com PKU no RS, sendo 19 obtidos para análise. Somente dois procuravam obter outras terapias que a FM. Nos outros 17 casos, uma solicitação de tratamento anterior fora concedida pela Secretaria Estadual de Saúde. Os réus incluem o Estado (n = 19), União (n = 1) e municípios (n = 4). Em 18/19 casos, os tribunais decidiram a favor dos demandantes. Violação do direito à saúde e interrupção do tratamento prestado pelo Estado foram os principais motivos para recorrer aos tribunais. Diferente de outras doenças genéticas, os pacientes com PKU buscam o meio jurídico para obter um produto já incluso na política de assistência farmacêutica nacional, sugerindo que falhas de gestão são um dos fatores desencadeantes da judicialização no país.

Adherence to Treatment of Phenylketonuria: A Study in Southern Brazilian Patients

Abstract Introduction: Phenylketonuria (PKU) is caused by the deficient activity of phenylalanine hydroxylase. Aim: To identify the factors associated with treatment adherence among patients with PKU seen at a southern Brazil reference center. Methodology: A cross-sectional, outpatient-based study including 56 patients with PKU (median age, 12 years) for whom a Phe-restrict diet plus specific metabolic formula have been prescribed. Patients were considered adherent or nonadherent depending on the median phenylalanine concentration for the 12 months prior to study and target levels of phenylalanine for each age range (<13 years = ≤360 µmol/L; ≥13 years = ≤900 µmol/L). Data were collected through a review of patient's medical records and a set of interviews with patients and their relatives. Results: Eighteen patients (32.1%; ≥13 years, 11) were classified as treatment adherent. Among all factors analyzed, only mental retardation, living with parents, and level of maternal education were associated with adherence to treatment. Conclusion: Our findings reinforce the importance of the family as promoting factor for treatment adherence.

Glycogen storage disease type I: clinical and laboratory profile / Doença de depósito de glicogênio tipo I: perfil clínico e laboratorial

OBJECTIVES: To characterize the clinical, laboratory, and anthropometric profile of a sample of Brazilian patients with glycogen storage disease type I managed at an outpatient referral clinic for inborn errors of metabolism. METHODS: This was a cross-sectional outpatient study based on a convenience sampling strategy. Data on diagnosis, management, anthropometric parameters, and follow-up were assessed. RESULTS: Twenty-one patients were included (median age 10 years, range 1-25 years), all using uncooked cornstarch therapy. Median age at diagnosis was 7 months (range, 1-132 months), and 19 patients underwent liver biopsy for diagnostic confirmation. Overweight, short stature, hepatomegaly, and liver nodules were present in 16 of 21, four of 21, nine of 14, and three of 14 patients, respectively. A correlation was found between height-for-age and BMI-for-age Z-scores (r = 0.561; p = 0.008). CONCLUSIONS: Diagnosis of glycogen storage disease type I is delayed in Brazil. Most patients undergo liver biopsy for diagnostic confirmation, even though the combination of a characteristic clinical presentation and molecular methods can provide a definitive diagnosis in a less invasive manner. Obesity is a side effect of cornstarch therapy, and appears to be associated with growth in these patients. .

OBJETIVOS: Caracterizar o perfil clínico, laboratorial e antropométrico de uma amostra de pacientes brasileiros com doença de depósito de glicogênio tipo I tratados em um ambulatório de referência para erros inatos do metabolismo. MÉTODOS: Este foi um estudo ambulatorial transversal com base em uma estratégia de amostragem de conveniência. Foram avaliados os dados com relação ao diagnóstico, tratamento, parâmetros antropométricos e acompanhamento. RESULTADOS: Foram incluídos 21 pacientes (idade média de 10 anos, faixa 1-25 anos de idade), e todos se encontravam em terapia de amido de milho cru. A idade média na época do diagnóstico foi de sete meses (faixa, 1-32 meses), e 19 pacientes foram submetidos a biópsia hepática para confirmação do diagnóstico. Sobrepeso, baixa estatura, hepatomegalia e nódulos hepáticos foram fatores presentes em 16 de 21, quatro de 21, nove de 14 e três de 14 pacientes, respectivamente. Foi encontrada uma correlação entre os escores z para peso para idade e IMC para idade (r = 0,561; p = 0,008). CONCLUSÕES: O diagnóstico da doença de depósito de glicogênio tipo I tem sido tardio no Brasil. A maioria dos pacientes foi submetida a confirmação do diagnóstico, apesar de o quadro clínico característico e os métodos moleculares poderem fornecer um diagnóstico definitivo de forma menos invasiva. Obesidade é um efeito colateral da terapia com amido de milho e parece estar associada a crescimento nesses pacientes. .

Responsividade à tetrahidrobiopterina em pacientes com deficiência de fenilalanina hidroxilase / Tetrahydrobiopterin responsiveness of patients with phenylalanine hydroxylase deficiency

OBJETIVO: Identificar indivíduos responsivos à tetrahibrobiopterina (BH4) em uma amostra de pacientes brasileiros com hiperfenilalaninemia por deficiência de fenilalanina-hidroxilase (HPA-PAH). MÉTODOS: Estudo intervencional, amostragem por conveniência. Para serem incluídos no estudo, os pacientes deveriam: possuir diagnóstico bioquímico de HPA-PAH; ter idade > 7 anos; estar em tratamento dietético; e apresentar níveis de fenilalanina (Phe) > 6 mg/dL em todas as medidas realizadas no ano anterior à inclusão no estudo. Os níveis de Phe foram determinados por meio de espectrometria de massas in tandem no dia anterior (dia 1) e nos pontos de hora 0, 4 e 8 h (dia 2) e 24 h (dia 3) após ingestão de BH4. Os critérios utilizados para definir responsividade ao BH4 foram: critério 1-redução > 30 por cento de Phe após 8 h da administração de BH4; e critério 2-redução > 30 por cento de Phe após 24 h da administração. RESULTADOS: Dezoito pacientes foram incluídos no estudo (mediana de idade = 14 anos, sexo masculino = 12). Cinco pacientes foram responsivos ao BH4, sendo três (forma clássica: um; forma leve: dois) de acordo com ambos os critérios, e dois (forma clássica: um; forma não definida: um) de acordo com o critério 2. Os níveis de Phe plasmáticos do dia 1 não demonstraram variação nos pontos de hora (p = 0,523). Entretanto, quando comparamos os níveis de Phe nos pontos de hora dos dias 1 e 2, encontramos uma variação significativa (p = 0,006). A análise da associação genótipo-fenótipo confirmou o caráter multifatorial da responsividade ao BH4. CONCLUSÃO: Os nossos achados estão de acordo com a literatura e indicam que um número relevante de pacientes brasileiros com HPA-PAH é responsivo à BH4.

OBJECTIVE: To identify patients responsive to tetrahydrobiopterin (BH4) in a sample of Brazilians with hyperphenylalaninemia due to phenylalanine hydroxylase deficiency (HPA-PAH). METHODS: Interventional study, convenience sampling. The inclusion criteria were: diagnosis of HPA-PAH; age > 7 years; phenylalanine-restricted diet and phenylalanine (Phe) levels > 6 mg/dL in all blood tests 1 year before inclusion. Blood samples were obtained the day before (day 1) and at 0, 4, 8 (day 2) and 24 h (day 3) after BH4 intake. Phe levels were measured using tandem mass spectrometry. The criteria used to define responsiveness to BH4 were: criterion 1- Phe reduction > 30 percent 8 h after BH4 administration; criterion 2 - Phe reduction > 30 percent 24 h after BH4 administration. RESULTS: Eighteen patients were enrolled (median age, 14 years; 12 boys). Five patients were responsive to BH4, 3 according to both criteria (one classical PKU, two mild PKU); and two according to criterion 2 (one classical PKU; one indefinite PKU type). There were no differences between Phe serum levels on day 1 and at the other time points (p = 0.523). However, Phe levels on days 1 and 2 were significantly different (p = 0.006). The analysis of the phenotype-genotype association confirmed its multifactorial character. CONCLUSION: A relevant number of Brazilian patients with HPA-PAH are responsive to BH4, in agreement with other studies in the literature.

Recomendações para o processo de obtenção do consentimento na pesquisa com seres humanos realizada no Hospital de Clínicas de Porto Alegre: [revisão] / Hospital de Clínicas de Porto Alegre directives for the informed consent process in human experimentation: [review]

São apresentadas recomendações institucionais para o processo de consentimento em pesquisas envolvendo seres humanos, especialmente para a elaboração e aplicação do Termo de Consentimento Livre e Esclarecido. Estas recomendações visam esclarecer os pesquisadores, com ênfase nos critérios utilizados pelo Comitê de Ética em Pesquisa do Hospital de Clínicas de Porto Alegre na avaliação de projetos, sobre aspectos fundamentais que devem ser levados em consideração quando da elaboração e obtenção do consentimento de potenciais participantes de um projeto de pesquisa.

Institutionals directives are proposed for the informed consent process in research involving human beings, especially for the development and implementation of the Informed Consent Form. These recommendations aim to clarify the researchers, using the Research Ethics Committee of Hospital de Clinicas de Porto Alegre in project review, on key aspects that must be taken into account when preparing and obtaining the consent of the prospects participants in a research project.

Fenilcetonúria no sistema único de saúde: avaliação de adesão ao tratamento em um centro de atendimento do Rio Grande do Sul / Phenylketonuria in the public health system: assessment of adherence to treatment in a medical care center in Rio Grande do Sul

Introdução: Fenilcetonúria (PKU) é um erro inato do metabolismo no qual ocorre um aumento dos níveis séricos do aminoácido fenilalanina. Objetivo: O presente estudo teve como objetivo avaliar a adesão ao tratamento de pacientes com PKU atendidos em um centro de referência do Rio Grande do Sul. Métodos: Estudo transversal de pacientes com PKU atendidos no ambulatório do Serviço de Genética Médica do Hospital de Clínicas de Porto Alegre, Brasil. Os parâmetros de adesão considerados foram a mediana de fenilalanina plasmática no último ano (critério 1); o consumo de fenilalanina (critério 2); o consumo de fórmula metabólica (critério 3); e o questionamento direto aos pacientes/familiares (critério 4). Resultados: Dos 45 pacientes incluídos no estudo, (mediana de idade de 11 anos), 51% eram do sexo masculino. De acordo com o critério utilizado, foram considerados aderentes 20 (critério 1); 16 (critério 2); 27 (critério 3) e 33 (critério 4) pacientes, respectivamente. Não houve concordância entre os critérios de adesão utilizados. Foram encontradas diferenças quando comparados os critérios 1 e 2 (P=0,027), critérios 1 e 3 (P=0,002) e critérios 3 e 4 (P=0,015). Conclusão: A adesão ao tratamento é dificilmente quantificada por parâmetros isolados. A distinta percepção por parte dos pacientes dá suporte à necessidade de busca de novas estratégias que promovam adesão, bem como do estudo de métodos que avaliem a mesma.

Introduction: Phenylketonuria (PKU) is an inborn error of metabolism in which there is an increase in the serum amino acid phenylalanine. Aim:This study aimed at evaluating the adherence to treatment of patients with PKU treated at a center of reference in Rio Grande do Sul. Methods: A cross-sectional study of PKU patients seen at the outpatient clinic of the Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Brazil. The parameters considered for adherence were: median of plasma phenylalanine in the past year (criterion 1); consumption of phenylalanine (criterion 2); consumption of metabolic formula (criterion 3); and direct questioning of patients/families (criterion 4). Results: Of the 45 patients included in the study (median age of 11 years), 51% were male. According to the criteria used, the following number of patients were considered compliant: 20 (criterion 1); 16 (criterion 2); 27 (criterion 3); and 33 (criterion 4), respectively. There was no agreement among the adherence criteria used. Differences were found when comparing criteria 1 and 2 (P=0.027), criteria 1 and 3 (P=0.002), and criteria 3 and 4 (P=0.015). Conclusion: Adherence to treatment is barely quantified by isolated parameters. The patients’ different perception support the need of searching for new strategies to promote adherence and also new methods of assessment.