INITIAL CLINICAL PRESENTATION IN CASES OF INBORN ERRORS OF METABOLISM IN A REFERENCE CHILDREN'S HOSPITAL: STILL A DIAGNOSTIC CHALLENGE. / APRESENTAÇÃO CLÍNICA INICIAL DOS CASOS DE ERROS INATOS DO METABOLISMO DE UM HOSPITAL PEDIÁTRICO DE REFERÊNCIA: AINDA UM DESAFIO DIAGNÓSTICO.

OBJECTIVE: To assess the initial clinical presentation of confirmed cases of inborn errors of metabolism (IEM) at a reference facility for pediatric care. METHODS: Cross-sectional, observational and descriptive study with data collection of outpatients, from January 2009 to December 2013. Inclusion criterion: referral to IEM investigation. Exclusion criterion: prior diagnosis of IEM. Analyzed variables: identification data; status of diagnostic investigation; family history of IEM; initial clinical presentation, laboratory abnormalities related to the hypothesis of IEM. Descriptive statistical methods were used in the data analysis. RESULTS: We included 144 patients in the study, of which 62.5% were male. The mean and median ages were, respectively, 4.3 ± 4.7 years and 2.6 years. Twelve patients (8.3%) had a confirmed diagnosis of IEM (three with aminoacidopathies, three with organic acidemias, two with urea cycle disorders and four with lysosomal storage diseases). Cognitive impairment and seizures were the initial signs and symptoms, followed by growth retardation, neuropsychomotor developmental delay, seizures and hepatomegaly. The main laboratory abnormalities in the diagnosis were hyperammonemia and metabolic acidosis. CONCLUSIONS: The diagnosis of IEM still creates challenges to the pediatric practice. In this study, we identified the following factors: difficulty to access specific laboratory tests, reduced number of experts and poor dissemination of knowledge among healthcare schools. The early diagnosis of IEM majorly impacts the treatment and prevention of sequelae and should be considered in the initial diagnostic hypotheses.

OBJETIVO: Avaliar a apresentação clínica inicial dos casos com diagnóstico confirmado de erros inatos do metabolismo (EIM) em um serviço de referência em atendimento pediátrico. MÉTODOS: Estudo clínico, observacional, com delineamento transversal e de coleta retrospectiva em consulta ambulatorial de 2009 a 2013. Critério de inclusão: paciente encaminhado para investigação de EIM. Critério de exclusão: diagnóstico prévio de EIM. Variáveis analisadas: dados de identificação; situação atual da investigação diagnóstica; história familiar; apresentação clínica inicial; alterações laboratoriais. Os dados foram analisados por meio de estatística descritiva. RESULTADOS: Incluídos 144 pacientes, sendo 62,5% do sexo masculino. A mediana de idade foi de 2,6 anos e a média de 4,3 ± 4,7 anos. Doze pacientes (8,3%) tiveram o diagnóstico confirmado (três com aminoacidopatias, três com acidemias orgânicas, dois com distúrbios do ciclo da ureia e quatro com doenças de depósito lisossômico). Déficit cognitivo e convulsões foram os sinais e sintomas iniciais; seguidos de retardo de crescimento, atraso do desenvolvimento neuropsicomotor, convulsões e hepatomegalia. As principais alterações laboratoriais encontradas foram hiperamonemia e acidose metabólica. CONCLUSÕES: O diagnóstico dos EIM ainda traz desafios à prática pediátrica. Neste estudo foram identificados os seguintes fatores: dificuldade de acesso aos exames laboratoriais específicos, reduzido número de especialistas e pouca difusão do conhecimento nas faculdades da área da saúde. O diagnóstico precoce dos EIM tem impacto fundamental no tratamento e prevenção das sequelas, devendo ser considerado já nas hipóteses diagnósticas iniciais.

Apresentação clínica inicial dos casos de erros inatos do metabolismo de um hospital pediátrico de referência: ainda um desafio diagnóstico / Initial clinical presentation in cases of inborn errors of metabolism in a reference children's hospital: still a diagnostic challenge

RESUMO Objetivo: Avaliar a apresentação clínica inicial dos casos com diagnóstico confirmado de erros inatos do metabolismo (EIM) em um serviço de referência em atendimento pediátrico. Métodos: Estudo clínico, observacional, com delineamento transversal e de coleta retrospectiva em consulta ambulatorial de 2009 a 2013. Critério de inclusão: paciente encaminhado para investigação de EIM. Critério de exclusão: diagnóstico prévio de EIM. Variáveis analisadas: dados de identificação; situação atual da investigação diagnóstica; história familiar; apresentação clínica inicial; alterações laboratoriais. Os dados foram analisados por meio de estatística descritiva Resultados: Incluídos 144 pacientes, sendo 62,5% do sexo masculino. A mediana de idade foi de 2,6 anos e a média de 4,3 ± 4,7 anos. Doze pacientes (8,3%) tiveram o diagnóstico confirmado (três com aminoacidopatias, três com acidemias orgânicas, dois com distúrbios do ciclo da ureia e quatro com doenças de depósito lisossômico). Déficit cognitivo e convulsões foram os sinais e sintomas iniciais; seguidos de retardo de crescimento, atraso do desenvolvimento neuropsicomotor, convulsões e hepatomegalia. As principais alterações laboratoriais encontradas foram hiperamonemia e acidose metabólica. Conclusões: O diagnóstico dos EIM ainda traz desafios à prática pediátrica. Neste estudo foram identificados os seguintes fatores: dificuldade de acesso aos exames laboratoriais específicos, reduzido número de especialistas e pouca difusão do conhecimento nas faculdades da área da saúde. O diagnóstico precoce dos EIM tem impacto fundamental no tratamento e prevenção das sequelas, devendo ser considerado já nas hipóteses diagnósticas iniciais.

ABSTRACT Objective: To assess the initial clinical presentation of confirmed cases of inborn errors of metabolism (IEM) at a reference facility for pediatric care. Methods: Cross-sectional, observational and descriptive study with data collection of outpatients, from January 2009 to December 2013. Inclusion criterion: referral to IEM investigation. Exclusion criterion: prior diagnosis of IEM. Analyzed variables: identification data; status of diagnostic investigation; family history of IEM; initial clinical presentation, laboratory abnormalities related to the hypothesis of IEM. Descriptive statistical methods were used in the data analysis. Results: We included 144 patients in the study, of which 62.5% were male. The mean and median ages were, respectively, 4.3 ± 4.7 years and 2.6 years. Twelve patients (8.3%) had a confirmed diagnosis of IEM (three with aminoacidopathies, three with organic acidemias, two with urea cycle disorders and four with lysosomal storage diseases). Cognitive impairment and seizures were the initial signs and symptoms, followed by growth retardation, neuropsychomotor developmental delay, seizures and hepatomegaly. The main laboratory abnormalities in the diagnosis were hyperammonemia and metabolic acidosis. Conclusions: The diagnosis of IEM still creates challenges to the pediatric practice. In this study, we identified the following factors: difficulty to access specific laboratory tests, reduced number of experts and poor dissemination of knowledge among healthcare schools. The early diagnosis of IEM majorly impacts the treatment and prevention of sequelae and should be considered in the initial diagnostic hypotheses.

[Enzyme replacement therapy for mucopolysaccharidoses I, II and VI: recommendations from a group of Brazilian F experts]. / Terapia de reposição enzimática para as mucopolissacaridoses I, II e VI: recomendações de um grupo de especialistas brasileiros.

Mucopolysaccharidoses (MPS) are rare genetic diseases caused by deficiency of specific lysosomal enzymes that affect catabolism of glycosaminoglycans (GAG). Accumulation of GAG in various organs and tissues in MPS patients results in a series of signs and symptoms, producing a multisystemic condition affecting bones and joints, the respiratory and cardiovascular systems and many other organs and tissues, including in some cases, cognitive performance. So far, eleven enzyme defects that cause seven different types of MPS have been identified. Before introduction of therapies to restore deficient enzyme activity, treatment of MPS focused primarily on prevention and care of complications, still a very important aspect in the management of these patients. In the 80's treatment of MPS with bone marrow transplantation/hematopoietic stem cells transplantation (BMT/HSCT) was proposed and in the 90's, enzyme replacement therapy (ERT),began to be developed and was approved for clinical use in MPS I, II and VI in the first decade of the 21st century. The authors of this paper are convinced that a better future for patients affected by mucopolysaccharidoses depends upon identifying, understanding and appropriately managing the multisystemic manifestations of these diseases. This includes the provision of support measures (which should be part of regular multidisciplinary care of these patients) and of specific therapies. Although inhibition of synthesis of GAG and the recovery of enzyme activity with small molecules also may play a role in the management of MPS, the breakthrough is the currently available intravenous ERT. ERT radically changed the setting for treatment of mucopolysaccharidosis I, II and VI in the last decade., Benefits can even be extended soon to MPS IV A (ERT for this condition is already in clinical development), with prediction for treatment of MPS III A and the cognitive deficit in MPS II by administration of the enzyme directly into the central nervous system (CNS). A large number of Brazilian services, from all regions of the country, already have experience with ERT for MPS I, II and VI. This experience was gained not only by treating patients but also with the participation of some groups in clinical trials involving ERT for these conditions. Summing up the three types of MPS, more than 250 patients have already been treated with ERT in Brazil. The experience of professionals coupled to the data available in international literature, allowed us to elaborate this document, produced with the goal of bringing together and harmonize the information available for the treatment of these severe and progressive diseases, which, fortunately, are now treatable, a situation which bring new perspectives for Brazilian patients, affected by these conditions.

Lesão renal aguda em crianças: incidência e fatores prognósticos em pacientes gravemente enfermos / Acute kidney injury in children: incidence and prognostic factors in critical ill patients

OBJETIVOS: Lesão renal aguda caracteriza-se pela redução súbita e, em geral, reversível da função renal com perda da capacidade de manutenção da homeostase do organismo. Em pediatria, as principais causas de lesão renal aguda são sepse, uso de drogas nefrotóxicas e isquemia renal nos pacientes criticamente enfermos. Nesses pacientes, a incidência de lesão renal aguda varia de 20 a 30 por cento, resultando em aumento da taxa de morbi-mortalidade de 40 a 90 por cento. Este estudo tem como objetivo avaliar a incidência de lesão renal aguda nos pacientes internados em unidade de terapia intensiva, classificar a gravidade da lesão renal aguda de acordo com o Pediatric Risk, Injury, Failure, Loss, End-Stage (pRIFLE), analisar a relação entre lesão renal aguda e a gravidade através do Pediatric Index of Mortality (PIM) e estudar os fatores prognósticos associados. MÉTODOS: Realizou-se um estudo prospectivo entre julho de 2008 a janeiro de 2009 dos pacientes internados na unidade de terapia intensiva pediátrica do Hospital Infantil Joana de Gusmão - Florianópolis (SC) - Brasil. Todos os pacientes foram analisados diariamente através do débito urinário e creatinina sérica e classificados de acordo com pRIFLE. RESULTADOS: No período de acompanhamento foram internadas 235 crianças. A incidência de lesão renal aguda foi de 30,6 por cento, sendo que o pRIFLE máximo durante a internação foi de 12,1 por cento para R, 12,1 por cento para I e 6,4 por cento para F. A taxa de mortalidade foi de 12,3 por cento. Os pacientes que evoluíram com lesão renal aguda apresentaram risco dez vezes maior de óbito em relação aos não expostos. CONCLUSÃO: Lesão renal aguda é uma entidade comum nos pacientes críticos. O diagnóstico precoce a e instituição imediata de medidas terapêuticas adequadas a cada situação clínica podem alterar o curso e a gravidade do envolvimento renal reduzindo a morbi-mortalidade do paciente.

OBJECTIVES: Acute kidney injury is characterized by sudden and generally revertible renal function impairment involving inability to maintain homeostasis. In pediatrics, the main causes of acute kidney injury are sepsis, use of nephrotoxic drugs and renal ischemia in critically ill patients. The incidence of acute kidney injury in these patients ranges from 20 to 30 percent, resulting in increased morbid-mortality, a 40 to 90 percent rate. This study aimed to evaluate the incidence of acute kidney injury in intensive care unit patients, to categorize the severity of the acute kidney injury according to the Pediatric Risk, Injury, Failure, Loss, End-Stage (pRIFLE), examine the relationship between the acute kidney injury and severity using the Pediatric Index of Mortality (PIM) and to analyze outcome predictors. METHODS: A prospective study of the patients admitted to the intensive care unit of Hospital Infantil Joana de Gusmão - Florianópolis / SC - Brazil was conducted between July 2008 and January 2009. Were evaluated daily the urine output and serum creatinine, and the patients were categorized according to the pRIFLE criteria. RESULTS: During the follow-up period, 235 children were admitted. The incidence of acute kidney injury was 30.6 percent, and the maximal pRIFLE score during hospitalization was 12.1 percent for R, 12.1 percent for I and 6.4 percent for F. The mortality rate was 12.3 percent. The patients who developed acute kidney injury had a ten times bigger risk of death versus the not exposed patients. CONCLUSIONS: Acute kidney injury is frequent in critically ill patients. Early diagnosis and prompt and appropriate therapy for each clinical aspect may change this condition's course and severity, and reduce the patients' morbidity and mortality.

Acute kidney injury in children: incidence and prognostic factors in critical ill patients. / Lesão renal aguda em crianças: incidência e fatores prognósticos em pacientes gravemente enfermos.

OBJECTIVES: Acute kidney injury is characterized by sudden and generally revertible renal function impairment involving inability to maintain homeostasis. In pediatrics, the main causes of acute kidney injury are sepsis, use of nephrotoxic drugs and renal ischemia in critically ill patients. The incidence of acute kidney injury in these patients ranges from 20 to 30%, resulting in increased morbid-mortality, a 40 to 90% rate. This study aimed to evaluate the incidence of acute kidney injury in intensive care unit patients, to categorize the severity of the acute kidney injury according to the Pediatric Risk, Injury, Failure, Loss, End-Stage (pRIFLE), examine the relationship between the acute kidney injury and severity using the Pediatric Index of Mortality (PIM) and to analyze outcome predictors. METHODS: A prospective study of the patients admitted to the intensive care unit of Hospital Infantil Joana de Gusmão - Florianópolis / SC - Brazil was conducted between July 2008 and January 2009. Were evaluated daily the urine output and serum creatinine, and the patients were categorized according to the pRIFLE criteria. RESULTS: During the follow-up period, 235 children were admitted. The incidence of acute kidney injury was 30.6%, and the maximal pRIFLE score during hospitalization was 12.1% for R, 12.1% for I and 6.4% for F. The mortality rate was 12.3%. The patients who developed acute kidney injury had a ten times bigger risk of death versus the not exposed patients. CONCLUSIONS: Acute kidney injury is frequent in critically ill patients. Early diagnosis and prompt and appropriate therapy for each clinical aspect may change this condition's course and severity, and reduce the patients' morbidity and mortality.

Mucopolysaccharidosis I, II, and VI: Brief review and guidelines for treatment.

Mucopolysaccharidoses (MPS) are rare genetic diseases caused by the deficiency of one of the lysosomal enzymes involved in the glycosaminoglycan (GAG) breakdown pathway. This metabolic block leads to the accumulation of GAG in various organs and tissues of the affected patients, resulting in a multisystemic clinical picture, sometimes including cognitive impairment. Until the beginning of the XXI century, treatment was mainly supportive. Bone marrow transplantation improved the natural course of the disease in some types of MPS, but the morbidity and mortality restricted its use to selected cases. The identification of the genes involved, the new molecular biology tools and the availability of animal models made it possible to develop specific enzyme replacement therapies (ERT) for these diseases. At present, a great number of Brazilian medical centers from all regions of the country have experience with ERT for MPS I, II, and VI, acquired not only through patient treatment but also in clinical trials. Taking the three types of MPS together, over 200 patients have been treated with ERT in our country. This document summarizes the experience of the professionals involved, along with the data available in the international literature, bringing together and harmonizing the information available on the management of these severe and progressive diseases, thus disclosing new prospects for Brazilian patients affected by these conditions.

Terapia de reposição enzimática para as mucopolissacaridoses I, II e VI: recomendações de um grupo de especialistas brasileiros / Enzyme replacement therapy for mucopolysaccharidoses I, II and VI: recommendations from a group of Brazilian F experts

As mucopolissacaridoses (MPS) são doenças genéticas raras causadas pela deficiência de enzimas lisossômicas específicas que afetam o catabolismo de glicosaminoglicanos (GAG). O acúmulo de GAG em vários órgãos e tecidos nos pacientes afetados pelas MPS resulta em uma série de sinais e sintomas, integrantes de um quadro clínico multissistêmico que compromete ossos e articulações, vias respiratórias, sistema cardiovascular e muitos outros órgãos e tecidos, incluindo, em alguns casos, as funções cognitivas. Já foram identificados 11 defeitos enzimáticos que causam sete tipos diferentes de MPS. Antes do advento de terapias dirigidas para a restauração da atividade da enzima deficiente, o tratamento das MPS tinha como principal foco a prevenção e o cuidado das complicações, aspecto ainda bastante importante no manejo desses pacientes. Na década de 80 foi proposto o tratamento das MPS com transplante de medula óssea/transplante de células tronco hematopoiéticas (TMO/TCTH) e na década de 90 começou o desenvolvimento da Terapia de Reposição Enzimática (TRE), que se tornou uma realidade aprovada para uso clínico nas MPS I, II e VI na primeira década do século 21. Os autores deste trabalho têm a convicção de que um melhor futuro para os pacientes afetados pelas MPS depende da identificação, compreensão e manejo adequado das manifestações multissistêmicas dessas doenças, incluindo medidas de suporte (que devem fazer parte da assistência multidisciplinar regular destes pacientes) e terapias específicas...

Mucopolysaccharidoses (MPS) are rare genetic diseases caused by deficiency of specific lysosomal enzymes that affect catabolism of glycosaminoglycans (GAG). Accumulation of GAG in various organs and tissues in MPS patients results in a series of signs and symptoms, producing a multisystemic condition affecting bones and joints, the respiratory and cardiovascular systems and many other organs and tissues, including in some cases, cognitive performance. So far, eleven enzyme defects that cause seven different types of MPS have been identified. Before introduction of therapies to restore deficient enzyme activity, treatment of MPS focused primnarily on prevention and care of complications, still a very important aspect in the management of these patients. In the 80's treatment of MPS with bone marrow transplantation/hematopoietic stem cells transplantation (BMT/HSCT) was proposed and in the 90's, enzyme replacement therapy (ERT),began to be developed and was approved for clinical use in MPS I, II and VI in the first decade of the 21st century. The authors of this paper are convinced that a better future for patients affected by mucopolysaccharidoses depends upon identifying, understanding and appropriately managing the multisystemic manifestations of these diseases. This includes the provision of support measures (which should be part of regular multidisciplinary care of these patients) and of specific therapies...

Mucopolysaccharidosis I, II, and VI: brief review and guidelines for treatment

Mucopolysaccharidoses (MPS) are rare genetic diseases caused by the deficiency of one of the lysosomal enzymes involved in the glycosaminoglycan (GAG) breakdown pathway. This metabolic block leads to the accumulation of GAG in various organs and tissues of the affected patients, resulting in a multisystemic clinical picture, sometimes including cognitive impairment. Until the beginning of the XXI century, treatment was mainly supportive. Bone marrow transplantation improved the natural course of the disease in some types of MPS, but the morbidity and mortality restricted its use to selected cases. The identification of the genes involved, the new molecular biology tools and the availability of animal models made it possible to develop specific enzyme replacement therapies (ERT) for these diseases. At present, a great number of Brazilian medical centers from all regions of the country have experience with ERT for MPS I, II, and VI, acquired not only through patient treatment but also in clinical trials. Taking the three types of MPS together, over 200 patients have been treated with ERT in our country. This document summarizes the experience of the professionals involved, along with the data available in the international literature, bringing together and harmonizing the information available on the management of these severe and progressive diseases, thus disclosing new prospects for Brazilian patients affected by these conditions.

A case report and review of hypokalemic paralysis secondary to renal tubular acidosis.

A 5-year-old girl with distal renal tubular acidosis (RTA) and hypokalemic muscle paralysis is reported. RTA is a known cause of hypokalemia, but in spite of the presence of persistent hypokalemia muscular paralysis is uncommon, rarely described in children, and the onset of paralysis may initially be misinterpreted particularly if the patient is attended by a physician who is not a pediatric nephrologist. Therefore parents must be informed about this possibility. Still, as the clinical appearance of hypokalemic paralysis is quite similar to familial hypokalemic periodic paralysis, and because the emergent and prophylactic treatment of the two disorders are quite different, we discuss the diagnostic evaluation and the treatment for both of them.

Pilot study with a glutamine-supplemented enteral formula in critically ill infants

Lactentes criticamente enfermos frequentemente apresentam desnutricao calorico-proteica em decorrencia de demandas aumentadas por sepse e falencia respiratoria. A glutamina e atualmente classificada como um aminoacido condicionalmente essencial, de interesse especial para pacientes graves. A imunomodulacao, a protecao intestinal, e a prevencao da deplecao proteica estao entre os argumentos citados a favor de sua utilizacao. Tendo como proposito averiguar a tolerancia e o impacto clinico da glutamina em lactentes graves, efetuou-se um estudo piloto prospectivo e randomizado com nove casos...