RESUMO
Glutathione synthetase deficiency (GSSD) is a rare inborn error of glutathione metabolism with autosomal recessive inheritance. The severe form of the disease is characterized by acute metabolic acidosis, usually present in the neonatal period with hemolytic anemia and progressive encephalopathy. A case of a male newborn infant who had severe metabolic acidosis with high anion gap, hemolytic anemia, and hyperbilirubinemia is reported. A high level of 5-oxoproline was detected in his urine and a diagnosis of generalized GSSD was made. DNA sequence analysis revealed the infant to be compound heterozygous with two mutations, c.738dupG in exon 8 of GSS gene resulting in p.S247fs and a repetitive sequence in exon 3 of GSS gene. Treatment after diagnosis of GSSD included supplementation with antioxidants and oral sodium hydrogen bicarbonate. However, he maintained a variable degree of metabolic acidosis and succumbed shortly after his parents requested discontinuation of therapy because of dismal prognosis and medical futility when he was 18 days old.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Glutationa Sintase/deficiência , Mutação , Acidose/etiologia , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Ácido Glutâmico/análise , Glutationa Sintase/genética , Glutationa Sintase/metabolismo , Humanos , Recém-Nascido , Masculino , Piroglutamato Hidrolase/deficiência , Piroglutamato Hidrolase/genética , Análise de Sequência de DNA/métodosRESUMO
Glutathione synthetase deficiency (GSSD) is a rare inborn error of glutathione metabolism with autosomal recessive inheritance. The severe form of the disease is characterized by acute metabolic acidosis, usually present in the neonatal period with hemolytic anemia and progressive encephalopathy. A case of a male newborn infant who had severe metabolic acidosis with high anion gap, hemolytic anemia, and hyperbilirubinemia is reported. A high level of 5-oxoproline was detected in his urine and a diagnosis of generalized GSSD was made. DNA sequence analysis revealed the infant to be compound heterozygous with two mutations, c.738dupG in exon 8 of GSS gene resulting in p.S247fs and a repetitive sequence in exon 3 of GSS gene. Treatment after diagnosis of GSSD included supplementation with antioxidants and oral sodium hydrogen bicarbonate. However, he maintained a variable degree of metabolic acidosis and succumbed shortly after his parents requested discontinuation of therapy because of dismal prognosis and medical futility when he was 18 days old.
Assuntos
Humanos , Masculino , Recém-Nascido , Erros Inatos do Metabolismo dos Aminoácidos/genética , Glutationa Sintase/deficiência , Mutação , Acidose/etiologia , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Ácido Glutâmico/análise , Glutationa Sintase/genética , Glutationa Sintase/metabolismo , Piroglutamato Hidrolase/deficiência , Piroglutamato Hidrolase/genética , Análise de Sequência de DNA/métodosRESUMO
Pyroglutamic acid (also known as 5-oxoproline) is an organic acid intermediate of the gamma-glutamyl cycle. Accumulation of pyroglutamic acid is a rare cause of high anion gap metabolic acidosis. In the pediatric population, the congenital form of pyroglutamic acidemia has been extensively described. However, there are scarce reports of the acquired form of this condition in children. The urine test for organic acids confirms the diagnosis of pyroglutamic acidemia. We report the case of a 16-month-old girl who developed transient 5-oxoprolinemia associated with malnutrition and the use of acetaminophen and ampicillin for the treatment of acute otitis media and abdominal pain. The patient received 21-hour course of n-acetylcysteine with improvement of metabolic acidosis. This report highligts the need of considering pyroglutamic acidemia in the differencial diagnosis for high anion gap metabolic acidosis in pediatric patients with malnutrition and other risk factors...
Assuntos
Humanos , Glutationa Sintase/deficiência , Cetose , Ácido PirrolidonocarboxílicoRESUMO
5-Oxoproline accumulates in glutathione synthetase deficiency, an autossomic recessive inherited disorder clinically characterized by hemolytic anemia, metabolic acidosis, and severe neurological symptoms whose mechanisms are poorly known. In the present study we investigated the effects of acute subcutaneous administration of 5-oxoproline to verify whether oxidative stress is elicited by this metabolite in vivo in cerebral cortex and cerebellum of 14-day-old rats. Our results showed that the acute administration of 5-oxoproline is able to promote both lipid and protein oxidation, to impair brain antioxidant defenses, to alter SH/SS ratio and to enhance hydrogen peroxide content, thus promoting oxidative stress in vivo, a mechanism that may be involved in the neuropathology of gluthatione synthetase deficiency.
Assuntos
Antioxidantes/metabolismo , Encefalopatias Metabólicas Congênitas/induzido quimicamente , Cerebelo/efeitos dos fármacos , Cérebro/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácido Pirrolidonocarboxílico/toxicidade , Fatores Etários , Animais , Antioxidantes/fisiologia , Encefalopatias Metabólicas Congênitas/metabolismo , Cerebelo/metabolismo , Cérebro/metabolismo , Modelos Animais de Doenças , Glutationa Sintase/deficiência , Peroxidação de Lipídeos/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Estresse Oxidativo/fisiologia , Ácido Pirrolidonocarboxílico/metabolismo , Ratos , Ratos WistarRESUMO
5-Oxoproline (pyroglutamic acid) accumulates in glutathione synthetase deficiency, an inborn metabolic defect of the gamma-glutamyl cycle. This disorder is clinically characterized by hemolytic anemia, metabolic acidosis and severe neurological disorders. Considering that the mechanisms of brain damage in this disease are poorly known, in the present study we investigated whether oxidative stress is elicited by 5-oxoproline. The in vitro effect of (0.5-3.0 mM) 5-oxoproline was studied on various parameters of oxidative stress, such as total radical-trapping antioxidant potential, total antioxidant reactivity, chemiluminescence, thiobarbituric acid-reactive substances, sulfhydryl content, carbonyl content, and 2',7'-dichlorofluorescein fluorescence, as well as on the activities of the antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase in cerebral cortex and cerebellum of 14-day-old rats. Total radical-trapping antioxidant potential and total antioxidant reactivity were significantly reduced in both cerebral structures. Carbonyl content and 2',7'-dichlorofluorescein fluorescence were significantly enhanced, while sulfhydryl content was significantly diminished. In contrast, chemiluminescence and thiobarbituric acid-reactive substances were not affected by 5-oxoproline. The activities of catalase, superoxide dismutase and glutathione peroxidase were also not altered by 5-oxoproline. These results indicate that 5-oxoproline causes protein oxidation and reactive species production and decrease the non-enzymatic antioxidant defenses in rat brain, but does not cause lipid peroxidation. Taken together, it may be presumed that 5-oxoproline elicits oxidative stress that may represent a pathophysiological mechanism in the disorder in which this metabolite accumulates.
Assuntos
Antioxidantes/metabolismo , Encefalopatias Metabólicas/metabolismo , Cerebelo/metabolismo , Córtex Cerebral/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácido Pirrolidonocarboxílico/farmacologia , Animais , Catalase/metabolismo , Cerebelo/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Glutationa Sintase/deficiência , Técnicas In Vitro , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
OBJECTIVE: The objective was to determine the long-term clinical outcome and the effects of treatment of patients with glutathione synthetase (GS) deficiency (n = 28). METHODS: The diagnosis was based on demonstration of a marked decrease in GS activity in erythrocytes or cultured fibroblasts in all patients and was supported by finding a decrease in erythrocyte or fibroblast glutathione, presence of 5-oxoprolinuria, or both. The treatment varied but usually included correction of acidosis and supplementation with vitamins C and/or E. RESULTS: Sixteen patients were severely affected with neurologic symptoms such as seizures and psychomotor retardation; 7 had died at the time of the study. None of the severely affected patients had been treated with both vitamins C and E from the neonatal period. No significant difference was found in GS activity between patients with or without neurologic symptoms or in erythrocyte or fibroblast glutathione levels. Five patients had recurrent bacterial infections. CONCLUSION: On the basis of clinical symptoms, patients with GS deficiency can be classified into 3 phenotypes: mild, moderate, and severe. Our results indicate that early supplementation with vitamins C and E may improve the long-term clinical outcome.
Assuntos
Glutationa Sintase/deficiência , Acidose/tratamento farmacológico , Adulto , Anemia Hemolítica/genética , Ácido Ascórbico/uso terapêutico , Criança , Pré-Escolar , Eritrócitos/enzimologia , Feminino , Fibroblastos/enzimologia , Genes Recessivos , Glutationa Sintase/genética , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Doenças do Sistema Nervoso/genética , Transtornos Psicomotores/genética , Fatores de Tempo , Vitamina E/uso terapêuticoRESUMO
Se estandarizaron las técnicas de actividad de g -glutamil cisteil sintetasa y glutatión sintetasa con el objetivo de estudiar los pacientes con deficiencia congénita de glutatión reducido. Los valores normales encontrados en nuestro laboratorio no presentaron diferencias significativas con los señalados por otros autores. Se estudiaron varios miembros de una familia con deficiencia de glutatión reducido. Los estudios bioquímicos excluyeron la posible deficiencia de glucosa-6-fosfato deshidrogenasa. En el propósito y un hermano (G.D.R.) se encontró deficiencia de glutatión sintetasa. Ambos presentan una anemia hemolítica congénita no esferocítica, con hemólisis crónica e íctero que se exacerba en el transcurso de procesos infecciosos y también litiasis vesicular. Ninguno presentó acidosis metabólica ni trastornos neurológicos progresivos, por lo que ambos son portadores de la forma benigna de la enfermedad. En el padre y otro hermano, los resultados del estudio hematológico y bioquímico indican que posiblemente son heterocigóticos para la deficiencia de esta enzima. Esta es la primera familia con deficiencia de glutatión sintetasa encontrada en nuestra población
Assuntos
Humanos , Feminino , Adulto , Anemia Hemolítica Congênita/genética , Glutamato-Cisteína Ligase/genética , Glutationa Sintase/deficiência , Glutationa Sintase/genética , Glutationa/deficiênciaRESUMO
A 45-month-old girl with 5-oxoprolinuria (pyroglutamic aciduria), hemolysis, and marked glutathione depletion caused by deficiency of glutathione synthetase was followed before and during treatment with ascorbate or N-acetylcysteine. High doses of ascorbate (0.7 mmol/kg per day) or N-acetylcysteine (6 mmol/kg per day) were given for 1 to 2 weeks without any obvious deleterious side effects. Ascorbate markedly increased lymphocyte (4-fold) and plasma (8-fold) levels of glutathione. N-Acetylcysteine also increased lymphocyte (3.5-fold) and plasma (6-fold) levels of glutathione. After these treatments were discontinued, lymphocyte and plasma glutathione levels decreased rapidly to pretreatment levels. Ascorbate treatment was extended for 1 year, and lymphocyte (4-fold) and plasma (2- to 5-fold) glutathione levels remained elevated above baseline. In parallel, the hematocrit increased from 25.4% to 32.6%, and the reticulocyte count decreased from 11% to 4%. The results demonstrate that ascorbate and N-acetylcysteine can decrease erythrocyte turnover in patients with hereditary glutathione deficiency by increasing glutathione levels.
Assuntos
Acetilcisteína/uso terapêutico , Ácido Ascórbico/uso terapêutico , Glutationa Sintase/deficiência , Pré-Escolar , Feminino , Glutationa Sintase/análise , Glutationa Sintase/sangue , Humanos , Linfócitos/enzimologia , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/tratamento farmacológico , Vitamina E/uso terapêuticoRESUMO
We have shown that in preterm infants, and during the third trimester of pregnancy, there is a limited flow of isotopic glycine nitrogen to urea. We interpreted this as indicating that the large metabolic demand for glycine made by the rapidly growing foetus exceeded the ability of the body to produce glycine endogenously. In pyroglutamic aciduria, an inborn error of metabolism, a deficiency of glutathione synthetase results in an increased urinary excretion of pyroglutamic acid. We reasoned that limited availability of glycine, a substrate of glutathione synthetase, would restrict flow through this enzyme and might thus result in increased urinary excretion of pyroglutamic acid. We have measured the urinary excretion of pyroglutamic acid in non-pregnant and pregnant women in the 1st, 2nd and 3rd trimester. There was a relatively small dirunal variation in pyroglutamic acid/creatinine and a single urine gave a representative value. The pyroglutamic acid excretion rose progressively as pregnancy advanced and by the third trimester was over 20 times greater than in the non-pregnant women. As only a portion of the pyroglutamic acid produced is normally excreted in the urine, it is not possible to exclude the possibility that the increased excretion reflects a change in the metabolism of pyroglutamic acid unrelated to glycine metabolism. However, we have found that in four different metabolic states in which the demand for glycine is enhanced, there is an increased pyroglutamic acid excretion. These results provide support for the postulate that glycine acts as a semi-essential amino acid, and suggest that the availability of glycine may be limited as pregnancy advances (AU)
Assuntos
Humanos , Feminino , Gravidez , Ácido Pirrolidonocarboxílico/metabolismo , Aminoácidos , Glicina/metabolismo , Jamaica , Terceiro Trimestre da Gravidez , Glutationa Sintase/deficiênciaRESUMO
We have studied a patient with 5-oxoprolinuria who presented with hemolysis and metabolic acidosis as a neonate; he has had normal growth and development to one year of age. Compensated hemolytic anemia persists, and he requires alkalinizing agents for correction of acidosis. Biochemical studies have confirmed that a deficiency of glutathione synthetase is responsible for the 5-oxoprolinuria. Genetic heterogeneity was apparent on comparative study of glutathione synthetase kinetics in cells from two patients with this disorder. The consequences of the deficiency of glutathione synthetase, decreased intracellular glutathione, and overproduction of 5-oxoproline are discussed with reference to the possible cellular roles of these compounds.