RESUMO
The gas chromatographic and mass spectrometric identification of lactyl lactate and succinyl lactate, both present in human urine, is described. In the gas chromatogram lactyl lactate (as TMS derivative) presented as two peaks: the L,L- and/or D,D-form as well as the D,L- and/or the L,D-enantiomer. Both L- and D-lactyl succinate were excreted simultaneously. Lactyl lactate was observed in many patients; succinyl lactate only a few times and only together with lactyl lactate. No correlation with (endogenous) urinary lactate could be established. Presumably these compounds are products of the intestinal bacteria.
Assuntos
Lactatos/urina , Erros Inatos do Metabolismo/urina , Succinatos/urina , Adulto , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Lactente , Masculino , Esforço FísicoRESUMO
Random urine samples from eight patients with propionicacidaemia were analyzed by gas chromatography and mass spectrometry in order to see if a consistent metabolite pattern with a high diagnostic value could be found. However, wide variations were observed. The presence of 3-hydroxypropionate and/or methylcitrate were considered to be diagnostic of propionyl-CoA carboxylase deficiency. In addition, samples from ketotic periods frequently contained 3-hydroxy-n-valerate and 3-oxo-n-valerate.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/urina , Propionatos/urina , Cromatografia Gasosa , Humanos , Lactente , Recém-Nascido , Espectrometria de MassasRESUMO
Urine samples from patients with propionic acidemia and from a patient with methylmalonic acidemia contained unknown non-acidic metabolites by gas chromatography/mass spectrometry after ethyl acetate extraction. It could be demonstrated by mass spectrometric studies and by synthesis of reference compounds that the major metabolite was 2-methyl-2,3-butanediol, while smaller amounts of 2,3-pentanediol were also present. These diols were present in abnormal amounts in these patients during attacks of metabolic decompensation.
Assuntos
Acidose/metabolismo , Butileno Glicóis/urina , Glicóis/urina , Malonatos/metabolismo , Propionatos/metabolismo , Cromatografia Gasosa , HumanosRESUMO
A report is given on a hitherto undescribed metabolic disorder, characterized clinically by fatal neonatal acidosis, hypoglycemia and a strong 'sweaty-feet' odour. Biochemical features were a massive urinary excretion of glutaric and lactic acids. Isobutyric, isovaleric and alpha-methylbutyric acids were also greatly increased, followed by adipic, ethylmalonic, alpha-hydroxybutyric, n-butyric, beta-hydroxybutyric, sebacic, suberic, propionic, alpha-hydroxyisovaleric and hexanoic acids. The serum level of glutaric acid was highly elevated. In the serum there were also abnormal levels of lactic, alpha-hydroxybutyric, adipic, suberic, p-hydroxyphenyllactic, myristic, hexadecenoic, palmitic, oleic and stearic acids. Plasma lysine and valine were also elevated. Degradation of 14C-labelled glutaric acid and 14C-labelled branched-chain amino acids, alpha-ketoisovaleric and alpha-ketoisocaproic acids in intact fibroblasts was decreased, whereas that of pyruvic acid was normal. The defect was tentatively supposed to be localized at the level of the metabolism of a range of acyl-CoA compounds. The name glutaric aciduria 'type II' is proposed for the patient's disease.
Assuntos
Erros Inatos do Metabolismo dos Carboidratos/urina , Glutaratos/urina , Aminoácidos/sangue , Erros Inatos do Metabolismo dos Carboidratos/sangue , Feminino , Humanos , Recém-Nascido , Lactatos/urina , Masculino , LinhagemRESUMO
Isovaleryl-beta-D-glucuronide, a new metabolite in the urine of patients with isovaleric acidemia, is described. Its gas chromatographic and mass spectrometric parameters are presented. In alkaline solution this glucuronide exhibited intramolecular rearrangements, resulting in isomers bearing the acyl moiety on C-2, C-3 and C-4. The isomers showed similar mass spectra but different positions on the gas chromatogram. In the index patient isovalerylglucuronide was a main metabolite, but the excretion was a transient phenomenon. Only traces of isovalerylglucuronide could also be detected in the urine of three other patients with isovaleric acidemia. The significance of this metabolite for the detoxication of isovalerate in isovaleric acidemia is discussed.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/urina , Glucuronatos/urina , Ácidos Pentanoicos/sangue , Valeratos/sangue , Valeratos/urina , Cromatografia Gasosa/métodos , Hemiterpenos , Humanos , Concentração de Íons de HidrogênioRESUMO
Octanoyl-beta-D-glucuronide was identified in the urine of five patients with hypoketotic hypoglycemia and dicarboxylic aciduria due to a defective beta-oxidation of medium-chain fatty acids. Two subjects who ingested large amounts of medium-chain triglycerides also excreted large amounts of the glucuronide. The substance was extracted from the urine with ethyl acetate and analyzed by: (1) gas chromatography/mass spectrometry (GC-MS) of the trimethylsilyl derivative and (2) preparative one-dimensional thin-layer chromatography followed by enzymatic hydrolysis with beta-glucuronidase and again GC-MS. A quantitative analysis was performed indirectly by measuring the urinary bound octanoate after the removal of octanoylcarnitine. Octanoylglucuronide represents an additional mechanism for the detoxification of octanoate; its formation may be of help for the maintenance of carnitine homeostasis in patients with medium-chain acyl-CoA dehydrogenase deficiency.
Assuntos
Acil-CoA Desidrogenases/deficiência , Caprilatos/urina , Ácidos Graxos/metabolismo , Erros Inatos do Metabolismo Lipídico/urina , Acil-CoA Desidrogenase , Carnitina/análogos & derivados , Carnitina/urina , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Concentração de Íons de Hidrogênio , Erros Inatos do Metabolismo Lipídico/enzimologiaRESUMO
An unknown acidic compound was detected in a number of urine samples from patients with a suspected metabolic disorder and some patients treated with chemotherapy. The structure of this compound has been characterized as (2-ethoxyethoxy)acetic acid, using a gas chromatography/mass spectrometry/computer system. The authentic compound was synthesized and compared with the unknown. Urinary (2-ethoxyethoxy)acetic acid is assumed to be formed endogenously from an exogenous precursor, probably 2-(2-ethoxyethoxy)ethanol.
Assuntos
Acetatos/urina , Etil-Éteres/urina , Acetatos/síntese química , Criança , Pré-Escolar , Cromatografia Gasosa , Etilenoglicóis , Feminino , Humanos , Lactente , Espectrometria de Massas , VolatilizaçãoRESUMO
A patient is described with glyceric acidemia and glyceric aciduria. The main clinical problems in infancy were severe metabolic acidosis and failure to thrive. The patient needs permanent treatment with bicarbonate. Hyperglycinemia, as described in the first case discovered elsewhere, was not present. The glyceric acid was found to have the D-configuration, as analyzed by capillary gas chromatography of its di-O-acetyl-l-menthyl ester. The abnormality may result from a defect in serine metabolism.
Assuntos
Acidose/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Ácidos Glicéricos/sangue , Acidose/etiologia , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Doença Crônica , Creatinina/urina , Cromatografia Gasosa-Espectrometria de Massas , Ácidos Glicéricos/urina , Humanos , Lactente , Masculino , EstereoisomerismoRESUMO
1. The metabolic fate of orally given deuterated L-tyrosine, 50 mg/kg body weight, was investigated in seven patients with tyrosinemia type I in order to obtain evidence that the primary defect is at the level of fumarylacetoacetase. 2. The absence of fumarylacetoacetase could be proved in liver biopsy specimens obtained from four patients. 3. All patients excreted deuterated succinylacetoacetate and deuterated succinylacetone was detected in six out of seven. The total amount of these compounds was rather low; maximal 8.3% of the dose. The peak of the excretion occurred 3-6 h after loading, indicating an endogenous formation of the metabolites. 4. All patients excreted deuterated 4-hydroxyphenyl acids, probably reflecting secondary 4-hydroxyphenylpyruvate dioxygenase deficiency connected with liver damage. 5. No evidence for other secondary routes of tyrosine metabolism was found.
Assuntos
Acetoacetatos/urina , Erros Inatos do Metabolismo dos Aminoácidos/urina , Heptanoatos/urina , Ácidos Heptanoicos/urina , Hidrolases/deficiência , Tirosina/sangue , 4-Hidroxifenilpiruvato Dioxigenase/deficiência , Deutério , Feminino , Humanos , Lactente , Fígado/enzimologia , Masculino , Tirosina/urinaAssuntos
Caproatos/urina , Ácidos Dicarboxílicos/urina , Ácidos Graxos/metabolismo , Adipatos/urina , Fenômenos Químicos , Química , Pré-Escolar , Cromatografia Gasosa , Gorduras na Dieta/administração & dosagem , Feminino , Humanos , Hidroxiácidos , Lactente , Masculino , Conformação Molecular , Oxirredução , TriglicerídeosRESUMO
Medium- and long-chain 3-hydroxymonocarboxylic acids represent intermediates in the beta-oxidation of fatty acids: they accumulate in the plasma of patients with an inherited deficiency of long-chain 3-hydroxyacylcoenzyme A dehydrogenase. 3-Hydroxy acids with chain lengths varying from 6 to 16 were synthesized by a Reformatzky reaction. Capillary gas chromatography of the pertrimethylsilyl derivatives was performed on a CP-Sil 19 CB column, coupled to a quadrupole mass spectrometer in the electron impact mode. Calculation of the retention indices showed that the separation of the 3-hydroxy acids from the homologous straight-chain fatty acids may be troublesome, stressing the need for mass spectrometric identification.
Assuntos
Ácidos Carboxílicos/análise , Cromatografia Gasosa-Espectrometria de Massas/métodos , Ácidos Carboxílicos/metabolismo , Ácidos Graxos/metabolismo , Cromatografia Gasosa-Espectrometria de Massas/instrumentação , Humanos , Plasma/químicaRESUMO
Two patients with methylmalonic acidaemia due to methylmalonyl-CoA mutase deficiency were studied for several years. Both exhibited at least two attacks of severe ketoacidosis, during which they excreted, in addition to methylmalonic acid, a number of abnormal compounds: 3-hydroxypropionic acid, 2-methyl-3-hydroxybutyric, 3-hydroxy-n-valeric acid, 3-oxo-n-valeric acid, 2-methyl-3-oxobutyric acid, citraconic acid and N-tiglyglycine. These compounds represent partly intermediary metabolites from the isoleucine degradation pathway and partly secondary metabolites of propionyl-CoA and tiglyl-CoA.
Assuntos
Acidose/urina , Erros Inatos do Metabolismo dos Aminoácidos/urina , Cetose/urina , Malonatos/urina , Ácido Metilmalônico/urina , Pré-Escolar , Cromatografia Gasosa , Feminino , Humanos , Cetose/etiologia , Espectrometria de MassasRESUMO
Inherited defects of mitochondrial beta-oxidation of fatty acids lead to hypoketotic hypoglycemia during prolonged fasting. Affected patients may present with episodes of a Reye-like illness or even sudden child death. The number of currently detected patients with medium-chain acyl-CoA dehydrogenase deficiency--the most common disease in this area--is indicative of a high frequency, possibly comparable to that of phenylketonuria. A comprehensive system of biochemical analyses is described, which enables the differential diagnosis of the various defects. An indispensable part of the diagnostic system is the gas chromatographic/mass spectrometric analysis of plasma and urinary organic acids. A correct diagnosis is a prerequisite for the installment of specific treatment.
Assuntos
Acil-CoA Desidrogenases/deficiência , Ácidos Graxos/metabolismo , Erros Inatos do Metabolismo Lipídico/diagnóstico , Mitocôndrias/metabolismo , Acil-CoA Desidrogenase , Acil-CoA Desidrogenases/metabolismo , Criança , Humanos , Erros Inatos do Metabolismo Lipídico/metabolismo , Modelos Biológicos , OxirreduçãoRESUMO
The profile of organic acids in plasma of patients with a deficiency of medium-chain acyl-CoA dehydrogenase (EC 1.3.99.3) was determined by gas-liquid chromatography of trimethylsilylated derivatives of the acids isolated by ethyl acetate extraction. All 13 patients had increased concentrations of free octanoate, cis-4-decenoate, and decanoate in their plasma. Cis-4-decenoate, an intermediary metabolite of linoleic acid, is pathognomonic of medium-chain acyl-CoA dehydrogenase deficiency. This metabolite does not accumulate in plasma after oral loading with medium-chain triglycerides, in contrast to octanoate and decanoate. Two postmortem plasma samples from victims of infant sudden-death syndrome had detectable octanoate and decanoate, but cis-4-decenoate could not be detected. The identification of cis-4-decenoate in plasma may be an aid in the diagnosis of an inherited defect in oxidation of medium-chain fatty acids.
Assuntos
Acil-CoA Desidrogenases/deficiência , Ácidos Graxos Monoinsaturados/sangue , Acil-CoA Desidrogenase , Caprilatos/sangue , Ácidos Decanoicos/sangue , Ácidos Graxos/sangue , Ácidos Graxos não Esterificados/sangue , Humanos , Lactente , Morte Súbita do Lactente/sangueRESUMO
A mentally retarded girl with epileptic seizures is described. Urinary organic acid screening revealed a massive excretion of glyceric acid, a normally barely detectable metabolite. Hyperglycinemia was not observed. Capillary gas chromatography of the O-acetylated (-)-menthyl ester of urinary glyceric acid showed the substance to have the D-configuration. The urinary D-glycerate excretion remained unaltered after an oral load with 200 mg/kg L-serine, but oral loading with fructose (1 g/kg) or dihydroxyacetone (1 g/kg) caused a sharp increase of the D-glycerate excretion. Treatment with a diet moderately restricted in fructose led to some clinical improvement as judged by subjective criteria. The metabolic lesion is thought to be located at some step of the fructose catabolic pathway, possibly at the level of hepatic triokinase deficiency.
Assuntos
Erros Inatos do Metabolismo dos Carboidratos/metabolismo , Frutose/metabolismo , Ácidos Glicéricos/sangue , Pré-Escolar , Di-Hidroxiacetona/metabolismo , Epilepsia/genética , Epilepsia/metabolismo , Feminino , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismoRESUMO
Analysis of urinary organic acids in patients admitted for screening for inborn errors of metabolism incidentally revealed the presence of abnormal amounts of 4-hydroxyphenyllactate (4-HPLA) and phenyllactate (PLA). These compounds are found in tyrosinaemia and phenylketonuria but in our patients such disorders could not be established. By means of configuration analysis it was shown that these 2-hydroxyacids consisted partly of the D-enantiomers, pointing to a bacterial origin. Endogenously formed urinary 2-hydroxyacids in tyrosinaemia or phenylketonuria consisted of only the L-enantiomers. Furthermore, the urine of a patient with an established short bowel syndrome contained a wide variety of bacterial amino acid metabolites, including 2-hydroxyisocaproic acid (2-HICA). In this case 2-HICA occurred predominantly in the D-form whereas in the urine of a patient with maple syrup urine disease this compound appeared to have the L-configuration.
Assuntos
Bactérias/metabolismo , Caproatos/urina , Lactatos/urina , Fenilpropionatos/urina , Erros Inatos do Metabolismo dos Aminoácidos/urina , Criança , Pré-Escolar , Cromatografia Gasosa , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro/urina , Masculino , Fenilcetonúrias/urina , Estereoisomerismo , Tirosina/sangueRESUMO
The urinary excretion of ethylmalonic acid was studied in various patients, including children with glutaric aciduria type II and with beta-ketothiolase deficiency. An increased excretion at a modest level was found in 20 out of 5000 children who were referred for screening of inherited metabolic disease. Two children were studied longitudinally, but no clue to the origin of ethylmalonic acid was found in these cases. It is concluded that follow-up investigation of abnormal ethylmalonic acid excretion is only indicated when additional organic acids such as dicarboxylic acids are excreted in large amounts.
Assuntos
Malonatos/urina , Erros Inatos do Metabolismo/urina , Acetil-CoA C-Aciltransferase/deficiência , Acidose/urina , Criança , Feminino , Humanos , Recém-Nascido , MasculinoRESUMO
Various types of dicarboxylic aciduria are known, most of them are accompanied by non-ketotic hypoglycaemia. For the differential diagnosis of these conditions several methods of investigation have been used: (1) analysis of urinary organic acids in both native and hydrolysed samples, (2) analysis of free and esterified carnitine, the latter by means of chromatographic separation and identification of acyl moieties, (3) analysis of plasma organic acids, including the so-called free fatty acids, (4) a prolonged fasting test with serial measurements of the aforementioned parameters and close monitoring of the blood glucose and (5) an oral loading test with medium chain triglycerides accompanied by the same measurements as those named in item (4). So far differentiation has been made between patients with a metabolite profile most probably characteristic of medium chain acyl-CoA dehydrogenase deficiency and other dicarboxylic acidurias, among the latter systemic carnitine deficiency. Patients belonging to the first group accumulate octanoate, decanoate and cis-4-decenoate in their plasma; they excrete hexanoylglycine, octanoylcarnitine and suberylglycine in addition to the usual C6-C10 dicarboxylic acids. There was a high prevalence of an increased plasma free fatty acid/3-hydroxybutyrate ratio.
Assuntos
Ácidos Dicarboxílicos/urina , Erros Inatos do Metabolismo/diagnóstico , Acil-CoA Desidrogenase , Acil-CoA Desidrogenases/deficiência , Adolescente , Carnitina/deficiência , Criança , Pré-Escolar , Diagnóstico Diferencial , Ácidos Graxos/metabolismo , Humanos , Hipoglicemia/diagnóstico , Lactente , Recém-Nascido , Erros Inatos do Metabolismo/metabolismoRESUMO
Isovaleric acidaemia was diagnosed in a 9-year-old girl with an unusual clinical presentation. She was severely mentally retarded, had an extreme growth retardation, bilateral cataracts, multiple fractures of the long bones, vitium cordis and malformations of the head. Frequent infections occurred since early childhood. The relevance of these findings is discussed.
Assuntos
Anormalidades Múltiplas , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Catarata/etiologia , Nanismo/etiologia , Deficiência Intelectual/etiologia , Ácidos Pentanoicos/sangue , Valeratos/sangue , Erros Inatos do Metabolismo dos Aminoácidos/sangue , Criança , Feminino , Glicina/análogos & derivados , Glicina/urina , Hemiterpenos , HumanosRESUMO
Two brothers, aged 7 and 5 years, who excreted large amounts of the leucine metabolites 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid, are described. The excretion of these metabolites could be enhanced by increasing the leucine intake. Restriction of the protein intake resulted in a marked reduction of the metabolite excretion. However, the excretion of the ultimate leucine metabolite, 3-hydroxy-3-methylglutaric acid, remained unchanged at a low level. The only clinical abnormality was speech retardation. A (partial) deficiency of 3-methylglutaconyl coenzyme A hydratase is proposed to be the most likely underlying defect.