RESUMEN
OBJECTIVE: In X-linked adrenoleucodystrophy (X-ALD) the peroxisomal beta-oxidation of saturated very long-chain fatty acids (VLCFAs; carbon length > 22 atoms) is impaired. These fatty acids accumulate in blood and tissues, in particular in the nervous system, adrenal cortex and testis. Most patients have a primary adrenocortical insufficiency with low levels of cortisol and dehydroepiandrosterone (DHEA) and its sulphate ester (DHEA-S), collectively called DHEA(S). Surprisingly, very low plasma levels of DHEA(S) may be found when plasma cortisol and ACTH levels are normal. In animal studies DHEA administration had a peroxisome proliferating effect and induced the expression of peroxisomal enzymes involved in the beta-oxidation of fatty acids. PATIENTS AND DESIGN: To study the effect of DHEA on fatty acids in X-ALD patients, we conducted a randomized double-blind study in which 14 men (age range 21-63 years) and one boy (12 years) received 50 mg of DHEA or placebo for 3 months, followed by a 1-month wash-out period, then 3 months of placebo or vice versa. RESULTS: A significant rise was seen in the plasma levels of DHEA-S, Delta4-androstenedione and IGF-I. The elevated saturated VLCFAs in plasma and erythrocytes did not change. However, in erythrocytes significant decreases were found in the total amount of fatty acids, in C16:0, C18:0 and in C20:4omega-6, C22:5omega-6, C18:1omega-9, C20:1omega-9 and C20:3omega-9. In plasma, decreases were found for C18:1omega-9 and increases for C20:1omega-9. CONCLUSIONS: Dehydroepiandrosterone supplementation for 3 months did not lower the elevated plasma levels of saturated very long-chain fatty acids in patients with X-linked adrenoleucodystrophy. Instead, a decrease in saturated and mono- and polyunsaturated fatty acids in erythrocytes and plasma was found. An increase of C20:1omega-9 was found in plasma only.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Adrenoleucodistrofia/tratamiento farmacológico , Deshidroepiandrosterona/administración & dosificación , Ácidos Grasos/sangre , Adyuvantes Inmunológicos/sangre , Administración Oral , Adrenoleucodistrofia/sangre , Adulto , Androstenodiona/sangre , Niño , Deshidroepiandrosterona/sangre , Método Doble Ciego , Eritrocitos/metabolismo , Ácidos Grasos Insaturados/sangre , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Masculino , Persona de Mediana EdadRESUMEN
Cardiomyopathy is common in infants with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Resolution of the cardiomyopathy can often be achieved by avoidance of fasting and changing from a conventional infant formula to one in which most long-chain fat is replaced by medium-chain triglycerides (MCT). It is uncertain whether the clinical improvement is due to the restriction of long-chain fat or whether the MCT have specific beneficial effects. To clarify this, the metabolic effects of MCT were examined in 5 patients. When given at around the level found in MCT-based infant formula, MCT had no effect on blood concentrations of ketone bodies, specific fatty acids or acylcarnitines. The present study cannot, however, exclude the possibility that MCT per se may have beneficial effects.
Asunto(s)
3-Hidroxiacil-CoA Deshidrogenasas/deficiencia , Carnitina/análogos & derivados , Alimentos Formulados , Triglicéridos/administración & dosificación , Triglicéridos/química , Carnitina/sangre , Niño , Preescolar , Ácidos Grasos no Esterificados/sangre , Humanos , Errores Innatos del Metabolismo/sangre , Errores Innatos del Metabolismo/dietoterapia , Errores Innatos del Metabolismo/fisiopatología , Mecánica RespiratoriaRESUMEN
Plasma and erythrocyte fatty acids have been measured in 9 patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency being treated with a low-fat diet. No significant abnormality was detected and in particular docosahexaenoic acid was not deficient.
Asunto(s)
3-Hidroxiacil-CoA Deshidrogenasas/deficiencia , 3-Hidroxiacil-CoA Deshidrogenasas/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/sangre , Errores Innatos del Metabolismo de los Aminoácidos/dietoterapia , Eritrocitos/metabolismo , Ácidos Grasos/sangre , Niño , Preescolar , Cromatografía de Gases , Dieta , Humanos , Concentración Osmolar , Plasma , Periodo PosprandialAsunto(s)
Trastorno Autístico/complicaciones , Trastorno Autístico/genética , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Adolescente , Adulto , Trastorno Autístico/diagnóstico , Trastorno Autístico/etiología , Electroencefalografía , Femenino , Duplicación de Gen , Pruebas Genéticas , Hospitales Psiquiátricos , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/etiología , Masculino , Persona de Mediana Edad , Países Bajos , SíndromeRESUMEN
Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid derived from dietary sources and broken down in the peroxisome to pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) via alpha-oxidation. Pristanic acid then undergoes beta-oxidation in peroxisomes. Phytanic acid naturally occurs as a mixture of (3S,7R,11R)- and (3R,7R,11R)-diastereomers. In contrast to the alpha-oxidation system, peroxisomal beta-oxidation is stereospecific and only accepts (2S)-isomers. Therefore, a racemase called alpha-methylacyl-CoA racemase is required to convert (2R)-pristanic acid into its (2S)-isomer. To further investigate the stereochemistry of the peroxisomal oxidation systems and their substrates, we have developed a method using gas-liquid chromatography-mass spectrometry to analyze the isomers of phytanic, pristanic, and trimethylundecanoic acid in plasma from patients with various peroxisomal fatty acid oxidation defects. In this study, we show that in plasma of patients with a peroxisomal beta-oxidation deficiency, the relative amounts of the two diastereomers of pristanic acid are almost equal, whereas in patients with a defect of alpha-methylacyl-CoA racemase, (2R)-pristanic acid is the predominant isomer. Furthermore, we show that in alpha-methylacyl-CoA racemase deficiency, not only pristanic acid accumulates, but also one of the metabolites of pristanic acid, 2610-trimethylundecanoic acid, providing direct in vivo evidence for the requirement of this racemase for the complete degradation of pristanic acid.
Asunto(s)
Ácidos Grasos/metabolismo , Oxigenasas de Función Mixta/metabolismo , Oxidorreductasas/metabolismo , Trastorno Peroxisomal/metabolismo , Ácido Fitánico/metabolismo , Racemasas y Epimerasas/metabolismo , Ácidos Grasos/sangre , Ácidos Grasos/química , Humanos , Oxigenasas de Función Mixta/deficiencia , Oxidación-Reducción , Oxidorreductasas/deficiencia , Trastorno Peroxisomal/sangre , Trastorno Peroxisomal/enzimología , Ácido Fitánico/sangre , Ácido Fitánico/química , Racemasas y Epimerasas/deficiencia , Enfermedad de Refsum/sangre , Enfermedad de Refsum/enzimología , Enfermedad de Refsum/metabolismo , EstereoisomerismoRESUMEN
BACKGROUND: The Joint metabolic clinic at the Prince of Wales Hospital was established in January 1997 to provide a comprehensive multi-disciplinary care to patients with inherited metabolic diseases (IMDs). Patients are referred from both within and outside our hospital. Until July, 2000, more than 40 patients and families with 20 different biochemical diagnoses attend the clinic for regular follow up. A pattern of more common IMDs among Hong Kong Chinese emerged from our case registry. In order to advance the understanding of Chinese metabolic diseases, we examined the molecular basis of those diseases with unique features in Chinese or were locally prevalent. Mutations were found in patients with primary carnitine deficiency, ornithine transcarbamylase deficiency, X-linked adrenoleukodystrophy, glutaric aciduria type I, and galactosemia. We also analyzed the mutations in multiple carboxylase deficiency and Niemann-pick type C on four families. CONCLUSIONS: Although IMDs are a significant cause of mortality and morbidity among pediatric patients, with a better understanding of the molecular genetics of these diseases, prenatal diagnosis of these common IMDs will be facilitated, which is currently the most effective way of controlling IMDs.
Asunto(s)
Errores Innatos del Metabolismo/epidemiología , Ácidos Grasos/metabolismo , Hong Kong/epidemiología , Humanos , Errores Innatos del Metabolismo/etnología , Errores Innatos del Metabolismo/genética , Mutación , Oxidación-ReducciónRESUMEN
In this work, NMR investigations that led to the discovery of a new inborn error of metabolism, beta-ureidopropionase (UP) deficiency, are reported. 1D (1)H-NMR experiments were performed using a patient's urine. 3-Ureidopropionic acid was observed in elevated concentrations in the urine spectrum. A 1D (1)H-(1)H total correlation spectroscopy (TOCSY) and two heteronuclear 2D NMR techniques (heteronuclear multiple bond correlation (HMBC) and heteronuclear single-quantum correlation (HSQC)) were used to identify the molecular structure of the compound that caused an unknown doublet resonance at 1.13 ppm. Combining the information from the various NMR spectra, this resonance could be assigned to 3-ureidoisobutyric acid. These observations suggested a deficiency of UP. With 1D (1)H-NMR spectroscopy, UP deficiency can be easily diagnosed. The (1)H-NMR spectrum can also be used to diagnose patients suffering from other inborn errors of metabolism in the pyrimidine degradation pathway.
Asunto(s)
Amidohidrolasas/deficiencia , Errores Innatos del Metabolismo/enzimología , Femenino , Humanos , Lactante , Espectroscopía de Resonancia Magnética , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/orinaRESUMEN
Desmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies. Patients with desmosterolosis have elevated levels of the cholesterol precursor desmosterol, in plasma, tissue, and cultured cells; this abnormality suggests a deficiency of the enzyme 3beta-hydroxysterol Delta24-reductase (DHCR24), which, in cholesterol biosynthesis, catalyzes the reduction of the Delta24 double bond of sterol intermediates. We identified the human DHCR24 cDNA, by the similarity between the encoded protein and a recently characterized plant enzyme--DWF1/DIM, from Arabidopsis thaliana--catalyzing a different but partially similar reaction in steroid/sterol biosynthesis in plants. Heterologous expression, in the yeast Saccharomyces cerevisiae, of the DHCR24 cDNA, followed by enzyme-activity measurements, confirmed that it encodes DHCR24. The encoded DHCR24 protein has a calculated molecular weight of 60.1 kD, contains a potential N-terminal secretory-signal sequence as well as at least one putative transmembrane helix, and is a member of a recently defined family of flavin adenine dinucleotide (FAD)-dependent oxidoreductases. Conversion of desmosterol to cholesterol by DHCR24 in vitro is strictly dependent on reduced nicotinamide adenine dinucleotide phosphate and is increased twofold by the addition of FAD to the assay. The corresponding gene, DHCR24, was identified by database searching, spans approximately 46.4 kb, is localized to chromosome 1p31.1-p33, and comprises nine exons and eight introns. Sequence analysis of DHCR24 in two patients with desmosterolosis revealed four different missense mutations, which were shown, by functional expression, in yeast, of the patient alleles, to be disease causing. Our data demonstrate that desmosterolosis is a cholesterol-biosynthesis disorder caused by mutations in DHCR24.
Asunto(s)
Colesterol/biosíntesis , Desmosterol/metabolismo , Genes Recesivos/genética , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/metabolismo , Mutación/genética , Proteínas del Tejido Nervioso , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Oxidorreductasas/genética , Secuencia de Aminoácidos , Animales , Preescolar , Colesterol/metabolismo , Clonación Molecular , Análisis Mutacional de ADN , Femenino , Flavina-Adenina Dinucleótido/metabolismo , Humanos , Recién Nacido , Masculino , Datos de Secuencia Molecular , NADP/metabolismo , Oxidorreductasas/química , Oxidorreductasas/metabolismo , Fenotipo , Plantas/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Alineación de SecuenciaRESUMEN
Peroxisomes are subcellular organelles with an indispensable role in cellular metabolism. The importance of peroxisomes for humans is stressed by the existence of a group of genetic diseases in humans in which there is an impairment in one or more peroxisomal functions. Most of these functions have to do with lipid metabolism including the alpha- and beta-oxidation of fatty acids. Here we describe the current state of knowledge about peroxisomal fatty acid alpha- and beta-oxidation with particular emphasis on the following: (1) the substrates beta-oxidized in peroxisomes; (2) the enzymology of the alpha- and beta-oxidation systems; (3) the permeability properties of the peroxisomal membrane and the role of the different transporters therein; (4) the interaction with other subcellular compartments, including the mitochondria, which are the ultimate site of NADH re-oxidation and full degradation of acetyl-CoA to CO(2) and water; and (5) the different disorders of peroxisomal alpha- and beta-oxidation.
Asunto(s)
Ácidos Grasos/metabolismo , Trastorno Peroxisomal/enzimología , Trastorno Peroxisomal/metabolismo , Peroxisomas/enzimología , Peroxisomas/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Transporte Biológico , Dióxido de Carbono/metabolismo , Carnitina/metabolismo , Carnitina O-Palmitoiltransferasa/metabolismo , Ácidos Grasos/química , Humanos , Membranas Intracelulares/metabolismo , Mitocondrias/enzimología , Mitocondrias/metabolismo , Mutación/genética , Trastorno Peroxisomal/genética , Racemasas y Epimerasas/deficiencia , Racemasas y Epimerasas/genética , Racemasas y Epimerasas/metabolismo , Especificidad por Sustrato , Agua/metabolismoRESUMEN
Two new individuals with alpha-NAGA deficiency are presented. The index patient, 3 years old, has congenital cataract, slight motor retardation and secondary demyelinisation. Screening of his sibs revealed an alpha-NAGA deficiency in his 7-year-old healthy brother who had no clinical or neurological symptoms. Both sibs are homozygous for the E325K mutation, the same genotype that was found in the most severe form of alpha-NAGA deficiency presenting as infantile neuroaxonal dystrophy. Thus, at the age of 7 years the same genotype of alpha-NAGA may present as a 'non-disease' (present healthy case) and can be associated with the vegetative state (the first two patients described with alpha-NAGA deficiency). The clinical heterogeneity among the 11 known individuals with alpha-NAGA deficiency is extreme, with a 'non-disease' (two cases) and infantile neuroaxonal dystrophy (two cases) at the opposite sides of the clinical spectrum. The broad spectrum is completed by a very heterogeneous group of patients with various degrees of epilepsy/behavioural difficulties/psychomotor retardation (four patients) and a mild phenotype in adults without overt neurological manifestations who have angiokeratoma and clear vacuolisation in various cell types (three cases). These observations are difficult to reconcile with a straightforward genotype-phenotype correlation and suggest that factors or genes other than alpha-NAGA contribute to the clinical heterogeneity of the 11 patients with alpha-NAGA deficiency.
Asunto(s)
Hexosaminidasas/deficiencia , Distrofias Neuroaxonales/enzimología , Células Cultivadas , Niño , Preescolar , Análisis Mutacional de ADN , Fibroblastos/enzimología , Fibroblastos/patología , Genotipo , Hexosaminidasas/genética , Humanos , Masculino , Mutación , Distrofias Neuroaxonales/genética , Oligosacáridos/análisis , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa , Piel/enzimología , alfa-N-AcetilgalactosaminidasaRESUMEN
BACKGROUND: Fatty acid research in schizophrenia has demonstrated an altered cell membrane phospholipid metabolism. Erythrocyte membrane phospholipid composition closest reflects that of neuronal membranes. METHODS: (Poly)(un)saturated fatty acid concentrations were measured in the erythrocyte membranes of 19, consecutively admitted, medicated young schizophrenic patients and then compared with matched control subjects. Psychiatric symptomatology was rated with the Positive and Negative Symptom Scale and Montgomery-Asberg Depression Rating Scale. Because diet, hormones, and cannabis influence fatty acid metabolism, we included these factors in our study. RESULTS: The most distinctive findings concerned the omega-3 series: C22:5 omega-3, C22:6 omega-3 (docosahexaenoic acid), and the sum of omega-3 fatty acids were significantly decreased. Interestingly, C20:4 omega-6 (arachidonic acid) was not lowered. In the omega-9 series, higher levels of C22:1 omega-9 and lower levels its elongation product, C24:1 omega-9 (nervonic acid), were found. Interestingly, the other arm of the desaturation-elongation sequence of C18:1 omega-9, C20:3 omega-9, was lower in patients. The total omega-9 fatty acid levels were also lower in patients. CONCLUSIONS: Significant differences in erythrocyte fatty acid composition were found. The differences were not due to diet or hormonal status and could not be explained by the medication or cannabis use. No consistent pattern emerged from the different fatty acid abnormalities and the clinical symptom scores.
Asunto(s)
Ácidos Docosahexaenoicos/sangre , Membrana Eritrocítica/metabolismo , Ácidos Grasos Insaturados/sangre , Esquizofrenia/metabolismo , Adolescente , Adulto , Cromatografía de Gases , Ingestión de Energía , Femenino , Estudios de Seguimiento , Hormonas/sangre , Humanos , Masculino , Estado Nutricional , Esquizofrenia/diagnóstico , Psicología del Esquizofrénico , Encuestas y CuestionariosRESUMEN
We identified a new peroxisomal disorder caused by a deficiency of the enzyme alpha-methylacyl-coenzyme A (CoA) racemase. Patients with this disorder show elevated plasma levels of pristanic acid and the bile acid intermediates di- and trihydroxycholestanoic acid (DHCA and THCA), which are all substrates for the peroxisomal beta-oxidation system. alpha-Methylacyl-CoA racemase plays an important role in the beta-oxidation of branched-chain fatty acids and fatty acid derivatives because it catalyzes the conversion of several (2R)-methyl-branched-chain fatty acyl-CoAs to their (2S)-isomers. Only stereoisomers with the 2-methyl group in the (S)-configuration can be degraded via beta-oxidation. In this study we used liquid chromatography/tandem mass spectrometry (LC-MS/MS) to analyze the bile acid intermediates that accumulate in plasma from patients with a deficiency of alpha-methylacyl-CoA racemase and, for comparison, in plasma from patients with Zellweger syndrome and patients with cholestatic liver disease.We found that racemase-deficient patients accumulate exclusively the (R)-isomer of free and taurine-conjugated DHCA and THCA, whereas in plasma of patients with Zellweger syndrome and patients with cholestatic liver disease both isomers were present. On the basis of these results we describe an easy and reliable method for the diagnosis of alpha-methylacyl-CoA racemase-deficient patients by plasma analysis. Our results also show that alpha-methylacyl-CoA racemase plays a unique role in bile acid formation. - Ferdinandusse, S., H. Overmars, S. Denis, H. R. Waterham, R. J. A. Wanders, and P. Vreken. Plasma analysis of di- and trihydroxycholestanoic acid diastereoisomers in peroxisomal alpha-methylacyl-CoA racemase deficiency. J. Lipid Res. 2001. 42: 137;-141.
Asunto(s)
Colestanoles/sangre , Trastorno Peroxisomal/diagnóstico , Racemasas y Epimerasas/deficiencia , Ácidos y Sales Biliares/sangre , Preescolar , Colestanoles/química , Colestasis Intrahepática/sangre , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Masculino , Oxidación-Reducción , Trastorno Peroxisomal/enzimología , Peroxisomas/enzimología , Espectrometría de Masa por Ionización de Electrospray , Estereoisomerismo , Síndrome de Zellweger/sangreRESUMEN
OBJECTIVE: To report late onset cerebral white matter disease as a distinctive phenotype in peroxisome biogenesis disorder (PBD). BACKGROUND: There is phenotypic and genetic overlap among the PBD known as Zellweger syndrome (ZS), infantile Refsum disease (IRD), and neonatal adrenoleukodystrophy (NALD). Distinctive external features are variable among these three disorders, and neurologic deficit has its onset at birth or in infancy. In a structured follow-up cohort of 25 patients with PBD, not including ZS, three patients had an unusual pattern of cerebral white matter disease with onset past the age of 1, not conforming to any of the classic PBD phenotypes. METHODS: Clinical phenotyping and follow-up, peroxisomal biochemical determinations in body fluids and fibroblasts, identification of affected PEX gene by genetic complementation in fibroblasts, and MRI studies. RESULTS: Two unrelated patients with PBD without distinctive external features had normal neurodevelopmental milestones during their first year, followed by rapid deterioration including severe hypotonic pareses, seizures, retinopathy, and deafness. A third patient initially diagnosed with IRD developed cerebral white matter degeneration in the third year of life, complicating the original diagnosis. MRI in all three patients showed cerebral demyelination with sparing of subcortical fibers and pronounced central cerebellar demyelination. CONCLUSIONS: Late-onset cerebral white matter disease may occur in PBD, either following IRD or following normal early development and in the absence of distinctive external features. Peroxisome biogenesis disorder should be included in the differential diagnosis of post-infantile onset of cerebral white matter disease
Asunto(s)
Imagen por Resonancia Magnética , Trastorno Peroxisomal/genética , Fenotipo , Proteínas/genética , Síndrome de Zellweger/genética , Encéfalo/patología , Preescolar , Femenino , Fibroblastos/metabolismo , Estudios de Seguimiento , Prueba de Complementación Genética , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Examen Neurológico , Endopeptidasa Neutra Reguladora de Fosfato PHEX , Trastorno Peroxisomal/diagnóstico , Síndrome de Zellweger/diagnósticoRESUMEN
Cardiolipin (CL) and phosphatidylglycerol (PG) are the major polyglycerophospholipids observed in mammalian tissues. CL is exclusively found in the inner mitochondrial membrane and is required for optimal function of many of the respiratory and ATP-synthesizing enzymes. The role of CL in oxidative phosphorylation is, however, not fully understood and although reduced CL content leads to aberrant cell function, no human disorders with a primary defect in cardiolipin metabolism have been described. In this paper we present evidence that patients with the rare disorder X-linked cardioskeletal myopathy and neutropenia (Barth syndrome, MIM 302060) have a primary defect in CL and PG remodeling. We investigated phospholipid metabolism in cultured skin fibroblasts of patients and show that the biosynthesis rate of PG and CL is normal but that the CL pool size is 75% reduced, indicating accelerated degradation. Moreover, the incorporation of linoleic acid, which is the characteristic acyl side chain found in mammalian CL, into both PG and CL is significantly reduced, whereas the incorporation of other fatty acids into these phospholipids is normal. We show that this defect was only observed in Barth syndrome patients' cells and not in cells obtained from patients with primary defects in the respiratory chain, demonstrating that the observed defect is not secondary to respiratory chain dysfunction. These results imply that the G4.5 gene product, which is mutated in Barth syndrome patients, is specifically involved in the remodeling of PG and CL and for the first time identify an essential factor in this important cellular process.
Asunto(s)
Cardiolipinas/metabolismo , Cardiomiopatía Dilatada/metabolismo , Miopatías Mitocondriales/metabolismo , Fosfatidilgliceroles/metabolismo , Fosfolípidos/metabolismo , Piel/metabolismo , Cardiomiopatía Dilatada/genética , Células Cultivadas , Fibroblastos/metabolismo , Humanos , Cinética , Miopatías Mitocondriales/genética , Mutación , Neutropenia/genética , Neutropenia/metabolismo , Fosfatidilgliceroles/química , Valores de Referencia , Síndrome , Cromosoma XAsunto(s)
3-Hidroxiacil-CoA Deshidrogenasas/deficiencia , Ácido Graso Desaturasas/deficiencia , Ácidos Grasos/metabolismo , Errores Innatos del Metabolismo Lipídico/diagnóstico , Acil-CoA Deshidrogenasa de Cadena Larga , Resultado Fatal , Femenino , Genes Recesivos , Humanos , Recién Nacido , Errores Innatos del Metabolismo Lipídico/terapia , 3-Hidroxiacil-CoA Deshidrogenasa de Cadena Larga , Masculino , Oxidación-ReducciónRESUMEN
A full-length cDNA clone encoding an isoform of human CTP synthetase (type II) was isolated. A 1761-nucleotide open reading frame which corresponds to a protein of 586 amino acids with a predicted molecular mass of 65678 Da was identified. The predicted protein sequence showed 74% identity with the translation product of a previously identified human CTP synthetase cDNA clone (type I). The function of the human cDNA encoding type II CTP synthetase was verified by successful complementation of the cytidine-requiring CTP synthetase deficient mutant JF618 of Escherichia coli. The gene encoding type II CTP synthetase has been localized on chromosome Xp22.
Asunto(s)
Ligasas de Carbono-Nitrógeno/genética , Isoenzimas/genética , Secuencia de Aminoácidos , Secuencia de Bases , Mapeo Cromosómico , ADN Complementario , Humanos , Datos de Secuencia Molecular , Sistemas de Lectura Abierta , Homología de Secuencia de Aminoácido , Cromosoma XRESUMEN
BACKGROUND: Patients with chronic fatigue syndrome (CFS) complain of muscle pain and impaired exercise tolerance. Previous studies show that this is due to systemic carnitine deficiency. We investigated the hypothesis that carnitine deficiency plays an important role in CFS in female CFS patients and compared their results with neighbourhood controls. METHODS: The level of total carnitine, free carnitine, acylcarnitine and carnitine esters were measured in 25 female CFS patients and 25 healthy matched neighbourhood controls in a blinded fashion. RESULTS: The previously reported decreased level of acylcarnitine in CFS patients was not confirmed. There were also no significant differences in levels of total carnitine, free carnitine and 20 carnitine esters between CFS patients and controls. CONCLUSIONS: The present study demonstrates that serum carnitine deficiency does not contribute to or causes the symptoms in many CFS patients.
Asunto(s)
Carnitina/deficiencia , Síndrome de Fatiga Crónica/sangre , Adulto , Carnitina/análogos & derivados , Carnitina/sangre , Estudios de Casos y Controles , Fatiga/sangre , Femenino , Humanos , Persona de Mediana Edad , Países Bajos , Sistema de Registros , Índice de Severidad de la Enfermedad , Método Simple Ciego , Estadísticas no ParamétricasRESUMEN
An 8-year-old boy is described with borderline cognitive impairment, cerebellar hypoplasia, a stroke-like episode, and venous thrombosis of the left leg after a period of immobilization. The pattern of multiple abnormalities in blood coagulation suggested carbohydrate-deficient glycoprotein syndrome type 1a. Isoelectric focusing of serum transferrin was abnormal. The activity of phosphomannomutase in leukocytes and fibroblasts was decreased. Mutation analysis of the PMM2 gene revealed the R141H/E151G genotype. These results confirm the presence of carbohydrate-deficient glycoprotein syndrome type 1a without severe psychomotor retardation.