RESUMEN
Persistent trimethylaminuria in children is caused by autosomal recessively inherited impairment of hepatic trimethylamine (TMA) oxidation due to deficiency of flavin monooxygenase 3 (FMO3) secondary to mutations in the FMO3 gene. Trimethylaminuria or 'fish odour syndrome' is due to excessive excretion into body fluids and breath of TMA derived from the enterobacterial metabolism of dietary precursors. The disorder is present from birth but becomes apparent as foods containing high amounts of choline or of trimethylamine N-oxide (TMAO) from marine (sea or saltwater) fish are introduced into the diet. In our experience, trimethylaminuria (FMO3 deficiency) in children is rare. We have compared the dynamics and diagnostic efficacy of choline loading with marine fish meals in six children with trimethylaminuria. Loading with a marine fish meal provides a simple and acceptable method for confirmation of diagnosis of suspected trimethylaminuria in children, with the effects being cleared more quickly than with a choline load test. However, oral loading with choline bitartrate allows estimation of residual oxidative capacity in vivo and is a useful adjunct to molecular studies. Patients homozygous for the 'common' P153L mutation in the FMO3 gene showed virtual complete lack of residual TMA N-oxidative capacity, consistent with a nonfunctional or absent FMO3 enzyme, whereas a patient with the M82T mutation showed some residual oxidative capacity. A patient compound heterozygous for two novel mutations, G193E and R483T, showed considerable residual N-oxidative capacity. A further patient, heterozygous for two novel sequence variations in the FMO3 gene, consistently showed malodour and elevated urinary TMA/TMAO ratios under basal conditions but a negative response to both choline and marine fish meal loading. Comparison of the effects of administration of antibiotics (metronidazole, amoxicillin, neomycin) on gut bacterial production of trimethylamine from choline showed they all reduced TMA production to a limited extent, with neomycin being most effective. 'Best-practice' diagnostic and treatment guidelines are summarized.
Asunto(s)
Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/terapia , Oxigenasas/deficiencia , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Colina/metabolismo , Colina/farmacología , Análisis Mutacional de ADN , Femenino , Productos Pesqueros , Humanos , Lactante , Masculino , Errores Innatos del Metabolismo/genética , Persona de Mediana Edad , MutaciónRESUMEN
Skeletal muscle function may be impaired in patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, but the value of L-carnitine in their long-term management is not clear. This study was designed as a pilot to examine the effects of L-carnitine on exercise tolerance in patients with MCAD deficiency. Four clinically asymoptomatic MCAD-deficient patients, aged 8 to 20 years, were studied. Incremental ramp exercise tests were carried out before and after 4 weeks' treatment with oral L-carnitine (100 mg/kg per day). During exercise without L-carnitine supplementation, plasma carnitine concentrations fell, associated with an increased excretion of urinary acylcarnitines, notably acetylcarnitine, hexanoylcarnitine and octanoylcarnitine. L-carnitine treatment prevented this fall in plasma carnitine and resulted in greater increases in excretion of acylcarnitines. All four patients showed biologically significant improvement in peak oxygen uptake (peak VO2, 18-32% improvement), VO2 at a heart rate of 170 beats/min (15-23% improvement), VO2 at anaerobic threshold (27-42% improvement), and/or oxygen pulse (10-32% improvement). Exercise tolerance in MCAD-deficient patients may be improved by short-term L-carnitine supplementation. This may be the direct result of improved intramitochondrial homeostasis induced by L-carnitine in removing accumulating acyl moieties.
Asunto(s)
Acil-CoA Deshidrogenasa/deficiencia , Carnitina/análogos & derivados , Carnitina/administración & dosificación , Ejercicio Físico , Errores Innatos del Metabolismo/tratamiento farmacológico , Errores Innatos del Metabolismo/metabolismo , Ácido 3-Hidroxibutírico/sangre , Ácidos/orina , Adolescente , Adulto , Umbral Anaerobio/efectos de los fármacos , Glucemia , Carnitina/orina , Niño , Prueba de Esfuerzo , Ácidos Grasos no Esterificados/sangre , Femenino , Humanos , Ácido Láctico/sangre , Estilo de Vida , Masculino , Proyectos PilotoRESUMEN
A 36-year follow-up on the original patient described with methylmalonic aciduria has shown that she has methylmalonyl-CoA apomutase deficiency. The main clinical problem associated with her methylmalonic aciduria is progressive renal impairment requiring commencement of haemodialysis at 42 years of age.
Asunto(s)
Enfermedades Renales/diagnóstico , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/enzimología , Metilmalonil-CoA Mutasa/deficiencia , Adulto , Biopsia , Femenino , Fibroblastos/metabolismo , Estudios de Seguimiento , Humanos , Diálisis Renal , Piel/patología , Resultado del TratamientoRESUMEN
The neurometabolic disorder glutaryl-CoA dehydrogenase (GCDH) deficiency is biochemically characterised by an accumulation of the marker metabolites 3-hydroxyglutaric acid, glutaric acid, and glutarylcarnitine. If untreated, the disease is complicated by acute encephalopathic crises, resulting in neurodegeneration of vulnerable brain regions, in particular the putamen. 3-hydroxyglutaric acid is considered the major neurotoxin in this disease. There are only preliminary data concerning glutaric acid concentrations in the brains of affected children and the distribution of 3-hydroxyglutaric acid and glutarylcarnitine has not been described. In the present study, we investigated post mortem the distribution of 3-hydroxyglutaric and glutaric acids as well as glutarylcarnitine in 14 different brain regions, internal organs, and body fluids (urine, plasma, cerebrospinal fluid) in a 14-year-old boy. 3-Hydroxyglutaric acid showed the highest concentration (62 nmol/g protein) in the putamen among all brain areas investigated. The glutarylcarnitine concentration was also highest in the putamen (7.1 nmol/g protein). We suggest that the regional-specific differences in the relative concentrations of 3-hydroxyglutaric acid contribute to the pattern of neuronal damage in this disease. These results provide an explanatory basis for the high vulnerability of the putamen in this disease, adding to the strong corticostriatal glutamatergic input into the putamen and the high excitotoxic susceptibility of neostriatal medium spiny neurons.
Asunto(s)
Encéfalo/metabolismo , Carnitina , Carnitina/análogos & derivados , Carnitina/metabolismo , Glutaratos , N-Metilaspartato/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/deficiencia , Putamen/metabolismo , Putamen/patología , Acidosis/metabolismo , Enfermedad Aguda , Adolescente , Anticonvulsivantes/uso terapéutico , Atrofia/patología , Encéfalo/enzimología , Carnitina/sangre , Carnitina/líquido cefalorraquídeo , Carnitina/orina , Análisis Mutacional de ADN , Resultado Fatal , Cromatografía de Gases y Espectrometría de Masas , Expresión Génica/genética , Glutaratos/sangre , Glutaratos/líquido cefalorraquídeo , Glutaratos/orina , Glutaril-CoA Deshidrogenasa , Humanos , Masculino , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/tratamiento farmacológico , Hipotonía Muscular/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Mutación Puntual/genética , Espasmo/tratamiento farmacológico , Espasmo/metabolismo , Vigabatrin/uso terapéuticoRESUMEN
This report describes three infants with genetic defects of carnitine-acylcarnitine translocase (CACT), an inner mitochondrial membrane carrier that is essential for long-chain fatty acid oxidation. Two of the patients were of European and Chinese origin; the third was from consanguineous Turkish parents. CACT activity was totally deficient in cultured skin fibroblasts from all three patients. Patient 1 was heterozygous for a paternal frameshift mutation (120 del T in exon 1) and a maternal lariat branch point mutation (-10 T --> G in intron 2). Patient 2 was heterozygous for the same lariat branch point (-10T --> G intron 2) mutation, derived from the father, and a maternal frameshift mutation (362 del G in exon 3). Patient 3 was homozygous for a frameshift mutation (306 del C in exon 3). All of the three frameshift mutations give rise to the same stop codon at amino acid residue 127 which is predicted to cause premature protein truncation. In addition, cDNA transcript analysis showed that these coding sequence mutations also increase the amount of aberrant mRNA splicing and exon skipping at distances up to 7.7 kb nucleotides from mutation sites. The data suggest that the stability of mRNA transcripts is decreased or the frequency of aberrant splicing is increased in the presence of CACT coding sequence mutations. These results confirm that CACT is the genetic locus of the recessive mutations responsible for the fatal defects of fatty acid metabolism previously associated with deficiency of translocase activity in these three cases.
Asunto(s)
Carnitina Aciltransferasas/deficiencia , Carnitina Aciltransferasas/genética , Codón/genética , Mutación/genética , Empalme del ARN/genética , ARN Mensajero/genética , Células Cultivadas , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
Previous reports of patients with 3-hydroxy-3-methylglutaric aciduria have described the occurrence of di-trimethylsilyl (TMS) and tri-TMS derivatives of 3-hydroxy-3-methylglutaric acid on analysis using gas chromatography and mass spectrometry, leading to difficulty in quantification and ambiguity in diagnosis. We have extracted organic acids from the urine of patients with 3-hydroxy-3-methylglutaric aciduria using a variety of procedures. Solvent extraction combined with hydrochloric acid/sodium chloride resulted in production of both di-TMS and tri-TMS derivatives of 3-hydroxy-3-methylglutaric acid and also mono-TMS and di-TMS derivatives of 3-hydroxyisovaleric acid. The effects were not abolished by heating. Use of sulphate-based reagents minimised artefact formation and use of DEAE-Sephadex anion exchange extraction resulted in single fully trimethylsilylated derivatives. Artefact formation during use of chloride-based reagents was abolished by pyridine added prior to trimethylsilylation. Chloride ions form adducts with hydroxyl groups in these 3-hydroxy-3-methyl carboxylic acids that prevent complete trimethylsilylation. Chloride-based reagents should be avoided in the solvent extraction of organic acids from physiological fluids or, if used, pre-treatment of the dried extract with pyridine is essential to avoid partial trimethylsilylation of 3-hydroxy-3-methyl carboxylic acids.
Asunto(s)
Meglutol/orina , Artefactos , Cromatografía por Intercambio Iónico , Cromatografía de Gases y Espectrometría de Masas , Humanos , Oxo-Ácido-Liasas/deficiencia , Compuestos de Trimetilsililo/químicaRESUMEN
We have previously shown that primary trimethylaminuria, or fish-odour syndrome, is caused by an inherited defect in the flavin-containing monooxygenase 3 (FMO3) catalysed N-oxidation of the dietary-derived malodorous amine, trimethylamine (TMA). We now report a novel causative mutation for the disorder identified in a young girl diagnosed by proton nuclear magnetic resonance (NMR) spectroscopy of her urine. Sequence analysis of genomic DNA amplified from the patient revealed that she was homozygous for a T to C missense mutation in exon 3 of the FMO3 gene. The mutation changes an ATG triplet, encoding methionine, at codon 82 to an ACG triplet, encoding threonine. A polymerase chain reaction/restriction enzyme-based assay was devised to genotype individuals for the FMO3Thr82 allele. Wild-type and mutant FMO3, heterologously expressed in a baculovirus-insect cell system, were assayed by ultraviolet spectrophotometry and NMR spectroscopy for their ability to catalyse the N-oxidation of TMA. The latter technique has the advantage of enabling the simultaneous, direct and semi-continuous measurement of both of the products, TMA N-oxide and NADP, and of one of the reactants, NADPH. Results obtained from both techniques demonstrate that the Met82Thr mutation abolishes the catalytic activity of the enzyme and thus represents the genetic basis of the disorder in this individual. The combination of NMR spectroscopy with gene sequence and expression technology provides a powerful means of determining genotype-phenotype relationships in trimethylaminuria.
Asunto(s)
Enfermedades Genéticas Congénitas/enzimología , Enfermedades Genéticas Congénitas/genética , Mutación/genética , Odorantes , Oxigenasas/genética , Adulto , Alelos , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Secuencia de Bases , Preescolar , Femenino , Enfermedades Genéticas Congénitas/orina , Genotipo , Humanos , Lactante , Metilaminas/sangre , Metilaminas/orina , Datos de Secuencia Molecular , Resonancia Magnética Nuclear Biomolecular , Oxigenasas/análisis , Oxigenasas/biosíntesis , Análisis de Secuencia de ADN , Síndrome , Treonina/genéticaRESUMEN
Polyethylene glycol-conjugated adenosine deaminase (pegademase) is used for enzyme replacement therapy for patients with severe combined immunodeficiency caused by adenosine deaminase deficiency. The entrapment of pegademase within human energy-replete carrier erythrocytes using a hypo-osmotic dialysis procedure was investigated with the objective of prolonging the in vivo circulatory half-life of the enzyme and maintaining therapeutic blood levels. Native unmodified adenosine deaminase (ADA) was similarly studied. The efficiency of pegademase entrapment was low (9%) whereas the entrapment of native unmodified ADA was substantial (50%), suggesting that the polyethylene glycol side-chains were impeding intracellular entrapment. The biochemical characteristics and the osmotic fragility of these carrier erythrocytes were not adversely affected by the entrapment of either pegademase or native ADA. In vivo survival studies of pegademase-loaded 51Cr-labelled carrier erythrocytes in an ADA-deficient adult patient showed a mean cell half-life of 16 d. Carrier erythrocyte-entrapped pegademase and native ADA had in vivo half-lives of 20 and 12.5 d, respectively, demonstrating that entrapment prolongs the half-life over that of plasma pegademase, which has a circulating half-life of 3-6 d. These results provide the basis for a more extensive clinical evaluation of carrier erythrocyte-entrapped native adenosine deaminase therapy.
Asunto(s)
Adenosina Desaminasa/administración & dosificación , Adenosina Desaminasa/deficiencia , Eritrocitos , Inmunodeficiencia Combinada Grave/tratamiento farmacológico , Adenosina Desaminasa/sangre , Adulto , Portadores de Fármacos , Femenino , Semivida , Humanos , Inmunodeficiencia Combinada Grave/enzimologíaRESUMEN
STUDY OBJECTIVE: To estimate the net financial benefit of neonatal screening for phenylketonuria (PKU): by a simple pooling of cost data from the literature; and by a more complex modelling approach. DESIGN: A systematic literature review was conducted to identify papers containing data on the monetary costs and benefits of neonatal screening for PKU. The methodological quality of the studies was appraised, and data were extracted on resource use and expenditure. Monetary data were converted to common currency units, and standardised to UK incidence rates. Net benefits were calculated for median, best case and worst case scenarios, and the effect of excluding poor quality studies and data was tested. The net benefit was also estimated from a model based on data from the literature and assumptions appropriate for the current UK situation. Extensive sensitivity analysis was conducted. MAIN RESULTS: The direct net benefit of screening based on the median costs and benefits from the 13 studies identified was 143,400 Pounds per case detected and treated (39,000 Pounds and 241,800 Pounds for worst case and best case scenarios respectively). The direct net benefit obtained by the modelling approach was lower at 93,400 Pounds per case detected and treated. Screening remained cost saving under sensitivity analysis, except with low residential care costs (less than 12,300 Pounds per annum), or very low incidence rates (less than 1 in 27,000). CONCLUSIONS: The economic literature on PKU screening is of variable quality. The two methods of secondary analysis lead to the same conclusion: that neonatal PKU screening is worthwhile in financial terms alone in the UK, and that it justifies the infrastructure for collecting and testing neonatal blood samples. This result cannot necessarily be extrapolated to other countries.
Asunto(s)
Tamizaje Neonatal/economía , Fenilcetonurias/economía , Análisis Costo-Beneficio , Humanos , Recién Nacido , Modelos Económicos , Fenilcetonurias/diagnóstico , Calidad de Vida , Años de Vida Ajustados por Calidad de Vida , Reino UnidoRESUMEN
The National Institute of Standards and Technology (NIST) Automated Mass Spectral Deconvolution and Identification System (AMDIS) is applied to a selection of data files obtained from the gas chromatography/mass spectrometry (GC/MS) analysis of urinary organic acids. Mass spectra obtained after deconvolution are compared with a special user library containing both the mass spectra and retention indices of ethoxime-trimethylsilyl (EO-TMS) derivatives of a set of organic acids. Efficient identification of components is achieved and the potential of the procedure for automated diagnosis of inborn errors of metabolism and for related research is demonstrated.
Asunto(s)
Autoanálisis , Ácidos Dicarboxílicos/orina , Cromatografía de Gases y Espectrometría de Masas/métodos , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/orina , Acil-CoA Deshidrogenasa , Preescolar , Ácido Graso Desaturasas/deficiencia , Glutaratos/orina , Hemiterpenos , Humanos , Lactante , Meglutol/orina , Ácido Metilmalónico/orina , Reconocimiento de Normas Patrones Automatizadas , Ácidos Pentanoicos/sangre , Propionatos/sangreRESUMEN
D-2-Hydroxyglutaric aciduria has been observed in patients with extremely variable clinical symptoms, creating doubt about the existence of a disease entity related to the biochemical finding. An international survey of patients with D-2-hydroxyglutaric aciduria was initiated to solve this issue. The clinical history, neuroimaging, and biochemical findings of 17 patients were studied. Ten of the patients had a severe early-infantile-onset encephalopathy characterized by epilepsy, hypotonia, cerebral visual failure, and little development. Five of these patients had a cardiomyopathy. In neuroimaging, all patients had a mild ventriculomegaly, often enlarged frontal subarachnoid spaces and subdural effusions, and always signs of delayed cerebral maturation. In all patients who underwent neuroimaging before 6 months, subependymal cysts over the head or corpus of the caudate nucleus were noted. Seven patients had a much milder and variable clinical picture, most often characterized by mental retardation, hypotonia, and macrocephaly, but sometimes no related clinical problems. Neuroimaging findings in 3 patients variably showed delayed cerebral maturation, ventriculomegaly, or subependymal cysts. Biochemical findings included elevations of D-2-hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid in both groups. Cerebrospinal fluid gamma-aminobutyric acid was elevated in almost all patients investigated. Urinary citric acid cycle intermediates were variably elevated. The conclusion of the study is that D-2-hydroxyglutaric aciduria is a distinct neurometabolic disorder with at least two phenotypes.
Asunto(s)
Corea/orina , Epilepsia/orina , Glutaratos/orina , Biomarcadores , Ventrículos Cerebrales/patología , Preescolar , Corea/diagnóstico por imagen , Corea/patología , Quistes , Epéndimo/patología , Epilepsia/diagnóstico por imagen , Epilepsia/patología , Salud de la Familia , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Hipotonía Muscular/diagnóstico por imagen , Hipotonía Muscular/patología , Hipotonía Muscular/orina , Fenotipo , Tomografía Computarizada por Rayos X , Baja Visión/diagnóstico por imagen , Baja Visión/patología , Baja Visión/orina , Ácido gamma-Aminobutírico/líquido cefalorraquídeoRESUMEN
Erythrocytes offer the exciting opportunity of being used as carriers of therapeutic agents. Encapsulation within erythrocytes will give the therapeutic agent a clearance equivalent to the normal life of the erythrocyte therefore maintaining therapeutic blood levels over prolonged periods and also giving a sustained delivery to the monocyte-macrophage system (reticulo-endothelial system). Both the dose and frequency of therapeutic interventions could thus be reduced. Ensuring a near-physiological survival time of carrier erythrocytes is essential to their successful use as a sustained drug delivery system, and this has not been demonstrated in man. In this study we assessed the survival in vivo of autologous unloaded energy-replete carrier erythrocytes in nine volunteers, using a standard 51Cr erythrocyte-labelling technique. Within 144 h after infusion there was a 3 to 49% fall in circulating labelled cells, followed thereafter by an almost complete return to initial circulating levels; surface counting demonstrated an initial sequestration of erythrocytes by the spleen and subsequent release. Mean cell life and cell half-life of the carrier erythrocytes were within the normal range of 89 to 131 days and 19 to 29 days respectively. These results demonstrate the viability of carrier erythrocytes as a sustained drug delivery system.
Asunto(s)
Portadores de Fármacos , Envejecimiento Eritrocítico , Adulto , Radioisótopos de Cromo , Diálisis , Recuento de Eritrocitos , Femenino , Corazón , Humanos , Pulmón , Masculino , Bazo , Factores de TiempoRESUMEN
BACKGROUND: Developments in screening technology and increased understanding of the natural history and treatment of inborn errors of metabolism (IEMs) have produced pressure to extend neonatal screening programmes. This review aims to assess the evidence for the appropriateness of such programmes. METHODS: A formal systematic literature review was conducted. Exclusion and inclusion criteria were used to select papers for critical appraisal by pairs of reviewers. Standard criteria were used to assess the appropriateness of neonatal screening for various IEMs. Site visits were conducted to assess new technologies for newborn screening. RESULTS: A total of 1866 papers were identified and 407 systematically selected for full critical appraisal. Published evidence confirmed that universal newborn screening for phenylketonuria (PKU) meets all of the screening criteria and justifies the expense and infrastructure necessary for the collection and testing of neonatal blood spots. There was insufficient evidence in the literature to assess the cost-effectiveness of screening for any other IEMs. There was reasonable evidence to support inclusion in extended neonatal screening of four other IEMs: biotinidase deficiency, congenital adrenal hyperplasia (CAH), medium-chain acyl CoA dehydrogenase (MCAD) deficiency and glutaric aciduria type 1 (GA1). CONCLUSIONS: Large-scale trials of screening for biotinidase, CAH, MCAD and GA1 should be conducted, with careful evaluation to establish their clinical effectiveness and cost-effectiveness in practice. Screening for the latter two disorders would be dependent upon the use of tandem mass spectrometry (tandem MS). The application of tandem MS to newborn screening requires further evaluation. The extension of neonatal screening programmes to other IEMs is not currently justified.
Asunto(s)
Medicina Basada en la Evidencia , Errores Innatos del Metabolismo/diagnóstico , Tamizaje Neonatal/normas , Evaluación de la Tecnología Biomédica , Humanos , Recién Nacido , Londres , Tamizaje Neonatal/métodos , Tamizaje Neonatal/estadística & datos numéricos , Evaluación de Programas y Proyectos de SaludRESUMEN
Proton NMR spectra of urine from subjects with multiple acyl-CoA dehydrogenase deficiency, caused by defects in either the electron transport flavoprotein or electron transport flavoprotein ubiquinone oxidoreductase, provide a characteristic and possibly diagnostic metabolite profile. The detection of dimethylglycine and sarcosine, intermediates in the oxidative degradation of choline, should discriminate between multiple acyl-CoA dehydrogenase deficiency and related disorders involving fatty acid oxidation. The excretion rates of betaine, dimethylglycine (and sarcosine) in these subjects give an estimate of the minimum rates of both choline oxidation and methyl group release from betaine and reveal that the latter is comparable with the calculated total body methyl requirement in the human infant even when choline intake is very low. Our results provide a new insight into the rates of in vivo methylation in early human development.
Asunto(s)
Acil-CoA Deshidrogenasas/deficiencia , Colina/metabolismo , Errores Innatos del Metabolismo Lipídico/enzimología , Acil-CoA Deshidrogenasas/metabolismo , Células Cultivadas , Niño , Creatina/orina , Creatinina/orina , Femenino , Humanos , Lactante , Recién Nacido , Errores Innatos del Metabolismo Lipídico/metabolismo , Errores Innatos del Metabolismo Lipídico/orina , Masculino , Metilación , Resonancia Magnética Nuclear Biomolecular , Oxidación-Reducción , ProtonesRESUMEN
Fumarase deficiency is a rare autosomal recessive disorder of the citric acid cycle causing severe neurological impairment. The cDNA for both the rat and human enzymes has been cloned previously and shown to encode a coding region of 1.46 kb. To scan for mutations in fumarase-deficient patients we amplified the coding region of fumarase from fibroblast/lymphoblast cDNA employing the oligonucleotide primers designed from the published human and rat cDNA sequence. We then directly sequenced the polymerase chain reaction product. In seven unrelated patients, we detected four missense mutations (A265T, D383V, F269C, K187R), a nonsense mutation (W458X), a 3-bp AAA insertion that introduces an additional lysine residue at codon 435, and a spontaneous new mutation resulting in a 74-bp deletion (66del74). Seven at-risk pregnancies were monitored with one prenatal diagnosis of fumarase deficiency by molecular analysis and favorable outcome of the other pregnancies as predicted by enzyme assay of cultured fetal cells or molecular analysis.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/genética , Fumarato Hidratasa/deficiencia , Fumarato Hidratasa/genética , Sustitución de Aminoácidos , Animales , Células Cultivadas , Análisis Mutacional de ADN , ADN Complementario/biosíntesis , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Mutación Puntual/genética , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Diagnóstico Prenatal/métodos , Ratas , Eliminación de SecuenciaRESUMEN
The effect of 4 weeks' treatment with oral-L-carnitine (100 mg/kg per day) on carnitine status and metabolic parameters during an incremental ramp exercise test in a 12-year-old girl with isovaleric acidaemia was examined to determine its possible therapeutic role. The maximum work rate achieved increased from 110 to 120 watts; oxygen consumption at anaerobic threshold from 600 to 800 L/min; peak oxygen consumption from 1270 to 1450 L/min; and oxygen pulse, a measure of cardiac output, from 7.0 to 8.1 L/beat. These changes were associated with increases in plasma and urinary free and acyl carnitine concentrations but no change in physical activity. This observed effect of L-carnitine on exercise performance may be on cardiac or skeletal muscle function or both. We conclude that, in this single patient with isovaleric acid-aemia, L-carnitine supplementation had objective benefits and further studies on more patients are warranted.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/tratamiento farmacológico , Carnitina/uso terapéutico , Ejercicio Físico , Leucina/metabolismo , Ácidos Pentanoicos/sangre , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Niño , Femenino , Hemiterpenos , HumanosRESUMEN
A breast-fed female infant died suddenly in the neonatal period at 31 hours of age with profound macrovesicular fatty infiltration of liver, kidney, and muscle on postmortem examination, suggestive of a defect in fatty acid beta-oxidation. Fatty acid and palmitoyl-carnitine oxidation studies and direct enzyme study of cultured skin fibroblasts suggested a deficiency in the oxidation of long-chain fatty acids distal to carnitine palmitoyl-transferase I and before long-chain acyl-coenzyme A dehydrogenases. Deficient activity of carnitine-acylcarnitine translocase was demonstrated with intermediate levels of activity in the infant's parents, consistent with autosomal recessive inheritance. Fatty acid oxidation studies showed deficient oxidation of fatty acids at all chain lengths from C10:0 to C24:0, with partially reduced oxidation of C26:0 fatty acid, indicating the occurrence of a single mitochondrial carnitine-acylcarnitine translocase and demonstrating the requirement in vivo for L-carnitine for mitochondrial transport of all medium- and long-chain fatty acyl moieties. The disorder may have been precipitated in this breast-fed infant by poor initial feeding, fasting stress, and the long-chain triglycerides of human milk. The severity of the disorder prompted prenatal diagnosis, and affected siblings were excluded in two subsequent pregnancies by fatty acid oxidation in cultured chorionic villus cells and amniocytes.