RESUMO
PURPOSE: To develop a safe and noninvasive in vivo assay of hepatic propionate oxidative capacity. METHODS: A modified 1-13C-propionate breath test was administered to 57 methylmalonic acidemia (MMA) subjects, including 19 transplant recipients, and 16 healthy volunteers. Isotopomer enrichment (13CO2/12CO2) was measured in exhaled breath after an enteral bolus of sodium-1-13C-propionate, and normalized for CO2 production. 1-13C-propionate oxidation was then correlated with clinical, laboratory, and imaging parameters collected via a dedicated natural history protocol. RESULTS: Lower propionate oxidation was observed in patients with the severe mut0 and cblB subtypes of MMA, but was near normal in those with the cblA and mut- forms of the disorder. Liver transplant recipients demonstrated complete restoration of 1-13C-propionate oxidation to control levels. 1-13C-propionate oxidation correlated with cognitive test result, growth indices, bone mineral density, renal function, and serum biomarkers. Test repeatability was robust in controls and in MMA subjects (mean coefficient of variation 6.9% and 12.8%, respectively), despite widely variable serum methylmalonic acid concentrations in the patients. CONCLUSION: Propionate oxidative capacity, as measured with 1-13C-propionate breath testing, predicts disease severity and clinical outcomes, and could be used to assess the therapeutic effects of liver-targeted genomic therapies for MMA and related disorders of propionate metabolism. TRIAL REGISTRATION: This clinical study is registered in www.clinicaltrials.gov with the ID: NCT00078078. Study URL: http://clinicaltrials.gov/ct2/show/NCT00078078.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Propionatos , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Biomarcadores , Testes Respiratórios , Humanos , Fígado , Ácido MetilmalônicoRESUMO
Newborn screening (NBS) is a well-established state-run public health program which has targeted the early identification of treatable diseases like classic galactosemia (CG) for over a decade. We describe the case of a symptomatic newborn with CG and an abnormal screen report, including positive DNA-based test, who still managed to fall through the cracks in a sub-optimally functioning NBS program, despite decades of screening experience. While much attention is paid to testing technology, this case illustrates basic minimum requirements a newborn screening program must fulfill to reliably identify and treat all affected individuals including minimum reporting requirements, case surveillance and a dedicated short-term follow-up program. In newborn screening, success is systematic.
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Galactosemias/diagnóstico , Triagem Neonatal , Saúde Pública , Galactosemias/epidemiologia , Galactosemias/genética , Humanos , Lactente , Recém-NascidoRESUMO
Hyperammonaemia in children can lead to grave consequences in the form of cerebral oedema, severe neurological impairment and even death. In infants and children, common causes of hyperammonaemia include urea cycle disorders or organic acidaemias. Few studies have assessed the role of extracorporeal therapies in the management of hyperammonaemia in neonates and children. Moreover, consensus guidelines are lacking for the use of non-kidney replacement therapy (NKRT) and kidney replacement therapies (KRTs, including peritoneal dialysis, continuous KRT, haemodialysis and hybrid therapy) to manage hyperammonaemia in neonates and children. Prompt treatment with KRT and/or NKRT, the choice of which depends on the ammonia concentrations and presenting symptoms of the patient, is crucial. This expert Consensus Statement presents recommendations for the management of hyperammonaemia requiring KRT in paediatric populations. Additional studies are required to strengthen these recommendations.
Assuntos
Terapia de Substituição Renal Contínua/métodos , Hiperamonemia/terapia , Diálise Peritoneal/métodos , Distúrbios Congênitos do Ciclo da Ureia/terapia , Arginina/uso terapêutico , Carnitina/uso terapêutico , Criança , Pré-Escolar , Técnica Delphi , Dieta com Restrição de Proteínas , Humanos , Terapia de Substituição Renal Híbrida , Hiperamonemia/metabolismo , Lactente , Recém-Nascido , Nutrição Parenteral/métodos , Fenilacetatos/uso terapêutico , Fenilbutiratos/uso terapêutico , Guias de Prática Clínica como Assunto , Diálise Renal/métodos , Benzoato de Sódio/uso terapêutico , Distúrbios Congênitos do Ciclo da Ureia/metabolismo , Complexo Vitamínico B/uso terapêuticoRESUMO
Urea cycle disorders (UCD) are rare inherited metabolic disorders caused by deficiencies of enzymes and transporters required to convert neurotoxic ammonia into urea. These deficiencies cause elevated blood ammonia, which if untreated may result in death, but even with optimal medical management, often results in recurrent brain damage. There are two major treatments for UCD: medical management or liver transplantation. Both are associated with mortality and morbidity but the evidence comparing outcomes is sparse. Thus, families face a dilemma: should their child be managed medically, or should they undergo a liver transplant? To (a) describe the factors that contribute to treatment choice among parents of children diagnosed with UCD and to (b) organise these factors into a conceptual framework that reflects how these issues interrelate to shape the decision-making experience of this population. Utilising grounded theory, qualitative data were collected through semi-structured interviews with parents (N = 35) and providers (N = 26) of children diagnosed with UCD and parent focus groups (N = 19). Thematic content analysis and selective and axial coding were applied. The framework highlights the life-cycle catalysts that frame families' personal perceptions of risks and benefits and describes the clinical, personal, social, and system factors that drive treatment choice including disease severity, stability, and burden, independence, peer experiences, and cost, coverage and access to quality care. Findings equip providers with evidence upon which to prepare for productive patient interactions about treatment options. They also provide a foundation for the development of patient-centred outcome measures to better evaluate effectiveness of treatments in this population.
Assuntos
Comportamento de Escolha , Tomada de Decisões , Pais/psicologia , Distúrbios Congênitos do Ciclo da Ureia/terapia , Adolescente , Criança , Pré-Escolar , Efeitos Psicossociais da Doença , Gerenciamento Clínico , Feminino , Grupos Focais , Humanos , Lactente , Recém-Nascido , Entrevistas como Assunto , Transplante de Fígado/métodos , Masculino , Pesquisa Qualitativa , Distúrbios Congênitos do Ciclo da Ureia/cirurgiaRESUMO
BACKGROUND: To improve our understanding of urea cycle disorders (UCDs) prospectively followed by two North American (NA) and European (EU) patient cohorts. AIMS: Description of the NA and EU patient samples and investigation of the prospects of combined and comparative analyses for individuals with UCDs. METHODS: Retrieval and comparison of the data from 1095 individuals (NA: 620, EU: 475) from two electronic databases. RESULTS: The proportion of females with ornithine transcarbamylase deficiency (fOTC-D), particularly those being asymptomatic (asfOTC-D), was higher in the NA than in the EU sample. Exclusion of asfOTC-D resulted in similar distributions in both samples. The mean age at first symptoms was higher in NA than in EU patients with late onset (LO), but similar for those with early (≤ 28 days) onset (EO) of symptoms. Also, the mean age at diagnosis and diagnostic delay for EO and LO patients were similar in the NA and EU cohorts. In most patients (including fOTC-D), diagnosis was made after the onset of symptoms (59.9%) or by high-risk family screening (24.7%), and less often by newborn screening (8.9%) and prenatal testing (3.7%). Analysis of clinical phenotypes revealed that EO patients presented with more symptoms than LO individuals, but that numbers of symptoms correlated with plasma ammonium concentrations in EO patients only. Liver transplantation was reported for 90 NA and 25 EU patients. CONCLUSIONS: Combined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilizing differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies.
Assuntos
Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Estudos de Coortes , Análise de Dados , Diagnóstico Tardio , Europa (Continente) , Feminino , Humanos , Recém-Nascido , Masculino , Triagem Neonatal/métodos , América do Norte , Doença da Deficiência de Ornitina Carbomoiltransferase/diagnóstico , Doença da Deficiência de Ornitina Carbomoiltransferase/metabolismo , Doenças Raras , Ureia/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/metabolismoRESUMO
The urea cycle disorders are a group of inherited biochemical diseases caused by a complete or partial deficiency of any one of the enzymes or transport proteins required to convert toxic ammonia into urea and to produce arginine and citrulline. The clinical manifestations of these disorders are mostly the result of acute or chronic hyperammonemia, which affects the central nervous system. Affected individuals can also develop hepatic dysfunction. These disorders can present at any age from the immediate newborn to later in life. Early diagnosis and treatment are key to improving outcomes.
Assuntos
Hiperamonemia/diagnóstico , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Amônia/sangue , Tratamento de Emergência/métodos , Humanos , Hiperamonemia/etiologia , Hiperamonemia/terapia , Lactente , Recém-Nascido , Ureia/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/terapiaRESUMO
ABL1 is a proto-oncogene well known as part of the fusion gene BCR-ABL1 in the Philadelphia chromosome of leukemia cancer cells. Inherited germline ABL1 changes have not been associated with genetic disorders. Here we report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. The variant c.734A>G (p.Tyr245Cys) was found to occur de novo or cosegregate with disease in five individuals (families 1-3). Additionally, a de novo c.1066G>A (p.Ala356Thr) variant was identified in a sixth individual (family 4). We overexpressed the mutant constructs in HEK 293T cells and observed increased tyrosine phosphorylation, suggesting increased ABL1 kinase activities associated with both the p.Tyr245Cys and p.Ala356Thr substitutions. Our clinical and experimental findings, together with previously reported teratogenic effects of selective BCR-ABL inhibitors in humans and developmental defects in Abl1 knockout mice, suggest that ABL1 has an important role during organismal development.
Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Transtornos Cromossômicos/genética , Anormalidades Craniofaciais/genética , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Proteínas de Fusão bcr-abl/genética , Mutação em Linhagem Germinativa/genética , Cardiopatias Congênitas/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Deformidades Congênitas dos Membros/genética , Animais , Linhagem Celular , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Knockout , Cromossomo Filadélfia/efeitos dos fármacos , Fosforilação/genética , Proto-Oncogene Mas , Transdução de Sinais/genéticaRESUMO
BACKGROUND: Inherited metabolic disorders (IMDs) are individually rare but collectively common disorders that frequently require rapid or urgent therapy. PURPOSE: This article provides a generalized approach to IMDs, as well as some investigations and safe therapies that may be initiated pending the metabolic consult. METHODS/SEARCH STRATEGY: An overview of the research supporting management strategies is provided. In addition, the newborn metabolic screen is reviewed. FINDINGS/RESULTS: Caring for infants with IMDs can seem difficult because each of the types is rarely seen; however, collectively the management can be seen as similar. IMPLICATIONS FOR PRACTICE: When an IMD is suspected, a metabolic specialist should be consulted for expert advice regarding appropriate laboratory investigations and management. Because rapid intervention of IMDs before the onset of symptoms may prevent future irreversible sequelae, each abnormal newborn screen must be addressed promptly. IMPLICATIONS FOR RESEARCH: Management can be difficult. Research in this area is limited and can be difficult without multisite coordination since sample sizes of any significance are difficult to achieve.
Assuntos
Erros Inatos do Metabolismo , Triagem Neonatal , Autopsia , Humanos , Recém-Nascido , Doenças do Recém-Nascido , Terapia Intensiva Neonatal , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/enfermagem , Erros Inatos do Metabolismo/terapia , Triagem Neonatal/métodos , Triagem Neonatal/normasRESUMO
Stable isotopes have greatly contributed to our understanding of nitrogen metabolism and the urea cycle. The measurement of urea flux via isotopic methods has traditionally been utilized to determine total body protein synthesis in subjects with an intact urea cycle. However, isotopic studies of nitrogen metabolism are also a useful adjunct to conventional clinical investigations in the diagnosis and management of the inherited hyperammonemias. Such studies offer a safe non-invasive method of measuring the reduction of in vivo hepatic ureagenesis, and thus may provide a more accurate measure of phenotypic severity in affected patients. In addition, isotopic methods are ideally suited to evaluate the efficacy of novel therapies to augment urea production.