RESUMEN
Dilated cardiomyopathy is a rare complication in propionic acidaemia (PA). Underlying pathophysiological mechanisms are poorly understood. We present a child of Pakistani consanguineous parents, diagnosed with late-onset PA at 18months of age. He presented a mild phenotype, showed no severe further decompensations, normal growth and psychomotor development on a low protein diet and carnitine supplementation. At 15years, a mildly dilated left ventricle was noticed. At 17years he presented after a 2-3month history of lethargy and weight loss with severe decompensated dilated cardiomyopathy. He was stabilised on inotropic support and continuous haemofiltration; a Berlin Heart biventricular assist device was implanted. He received d,l-hydroxybutyrate 200mg/kg/day, riboflavin and thiamine 200mg/day each and coenzyme Q10 (CoQ10). Myocardial biopsy showed endocardial fibrosis, enlarged mitochondria, with atypical cristae and slightly low respiratory chain (RC) complex IV activity relative to citrate synthase (0.012, reference range 0.014-0.034). Myocardial CoQ10 was markedly decreased (224pmol/mg, reference range 942-2738), with a marginally decreased white blood cell level (34pmol/mg reference range 37-133). The dose of CoQ10 was increased from 1.5 to 25mg/kg/day. Cardiomyopathy slowly improved allowing removal of the external mechanical cardiac support after 67days. We demonstrate for the first time low myocardial CoQ10 in cardiomyopathy in PA, highlighting secondary mitochondrial impairment as a relevant causative mechanism. According to these findings, a high-dose CoQ10 supplementation could be a potential adjuvant therapeutic to be considered in PA-related cardiomyopathy.
Asunto(s)
Cardiomiopatías/complicaciones , Mitocondrias/química , Miocardio/patología , Acidemia Propiónica/tratamiento farmacológico , Acidemia Propiónica/fisiopatología , Ubiquinona/análogos & derivados , Vitaminas/uso terapéutico , Adolescente , Biopsia , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/patología , Humanos , Lactante , Masculino , Resultado del Tratamiento , Ubiquinona/análisis , Ubiquinona/uso terapéuticoAsunto(s)
Acil-CoA Deshidrogenasa/deficiencia , Glicina/análogos & derivados , Enfermedades Metabólicas/diagnóstico , Tamizaje Neonatal/métodos , Técnicas de Laboratorio Clínico , Glicina/análisis , Glicina/orina , Humanos , Recién Nacido , Estudios Multicéntricos como Asunto , Proyectos Piloto , Sensibilidad y Especificidad , Reino UnidoRESUMEN
A nonsense mutation (c.729C>A, Y243X) in exon 7 of the PDHA1 gene in a patient with pyruvate dehydrogenase deficiency results in aberrant splicing of the primary transcript with production of stable mRNAs which lack either both exons 6 and 7 or exon 7 alone. Transfection and expression of genomic constructs covering exons 5 to 8 of the mutant PDHA1 gene reproduced this aberrant splicing in vitro. The same pattern of abnormal splicing was found when a silent mutation was introduced at the same position. Both the nonsense and silent mutations alter a strong consensus site for the binding of SRp40, suggesting that they may interfere with an exonic splicing enhancer in exon 7 of the gene. However, this appears to affect splicing of not only exon 7, but also the adjacent upstream exon. The splice acceptor site of intron 5 has weak homology to the consensus sequence and this may contribute to the combined splicing defect.
Asunto(s)
Codón sin Sentido , Elementos de Facilitación Genéticos , Piruvato Deshidrogenasa (Lipoamida)/genética , Empalme del ARN/genética , Animales , Secuencia de Bases , Células COS , Células Cultivadas , Chlorocebus aethiops , ADN/genética , Exones , Vectores Genéticos , Humanos , Mutagénesis Sitio-Dirigida , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/enzimología , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , TransfecciónAsunto(s)
Amidohidrolasas/deficiencia , Encefalopatías Metabólicas Innatas/enzimología , Encefalopatías Metabólicas Innatas/fisiopatología , Epilepsia/enzimología , Predisposición Genética a la Enfermedad/genética , Mutación Missense/genética , Acetilación , Adolescente , Amidohidrolasas/genética , Aminoácidos/orina , Encéfalo/enzimología , Encéfalo/patología , Encéfalo/fisiopatología , Química Encefálica/genética , Encefalopatías Metabólicas Innatas/genética , Preescolar , Análisis Mutacional de ADN , Epilepsia/genética , Epilepsia/fisiopatología , Femenino , Marcadores Genéticos/genética , Humanos , Lactante , Imagen por Resonancia Magnética , MasculinoRESUMEN
Alkaptonuria (endogenous ochronosis) is a rare metabolic disorder caused by a deficiency of homogentisic acid oxidase, an enzyme responsible for the metabolic degradation of tyrosine. Patients with alkaptonuria commonly present with joint pain owing to degenerative arthritis. Other affected patients may present with pigmentation of the ear cartilage and sclera. This article reports a case of aortic stenosis associated with ochronosis in a 48-year-old man who presented with severe cardiac failure. He had no previous diagnosis of alkaptonuria, which was confirmed by mass spectrometry analysis of urine. The pathogenesis of cardiovascular ochronosis is unclear, but is probably related to the extensive extracellular deposits of ochronotic pigment in the cardiac tissue.
Asunto(s)
Estenosis de la Válvula Aórtica/etiología , Ocronosis/complicaciones , Estenosis de la Válvula Aórtica/patología , Insuficiencia Cardíaca/etiología , Humanos , Masculino , Persona de Mediana Edad , Ocronosis/diagnóstico , Ocronosis/patologíaRESUMEN
At a tertiary referral centre, just over 50% of patients with plasma ammonia values over 200 micro mol/l had inborn errors of metabolism. To distinguish artefactual high values from those requiring treatment, the measurement should be repeated immediately if the result is above 200 micro mol/l and at lower concentrations if the patient is encephalopathic.
Asunto(s)
Amoníaco/sangre , Hiperamonemia/etiología , Humanos , Hiperamonemia/sangre , Manejo de Especímenes/métodosRESUMEN
BACKGROUND: Recurrent and persistent hypoketotic, hypofattyacidaemic hypoglycaemia in infancy and childhood is most frequently due to hyperinsulinism of infancy. This biochemical profile can also be due to non-islet cell tumour hypoglycaemia or circulating insulin-receptor autoantibodies. Hyperinsulinaemic hypoglycaemia is also seen in children with the Beckwith-Wiedemann syndrome, where it is usually transient. METHODS/RESULTS: We report a novel case of child with hemihypertrophy and severe persistent hypoketotic, hypofattyacidaemic hypoinsulinaemic hypoglycaemia. No 'big' pro-IGF2 forms or circulating insulin-receptor antibodies were found. Glucose and protein isotope turnover studies showed marked suppression of hepatic glucose production during fasting. There was no evidence for constitutive autophosphorylation of the insulin or IGF-1 receptor, and no evidence for up-regulation of IGF-1 receptor. CONCLUSION: The precise pathophysiology of this novel case is still unclear.
Asunto(s)
Anomalías Múltiples/patología , Ácidos Grasos/sangre , Hipoglucemia/sangre , Hipoglucemia/complicaciones , Insulina/sangre , Cuerpos Cetónicos/sangre , Autoanticuerpos/sangre , Glucemia/metabolismo , Preescolar , Ayuno , Glucagón/administración & dosificación , Glucosa/biosíntesis , Humanos , Hipertrofia , Hipoglucemia/dietoterapia , Inyecciones Intravenosas , Anticuerpos Insulínicos/sangre , Factor II del Crecimiento Similar a la Insulina , Hígado/metabolismo , Masculino , Fosforilación , Precursores de Proteínas/sangre , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , SíndromeRESUMEN
Hyperinsulinism of infancy is caused by inappropriate insulin secretion in pancreatic beta-cells, even when blood glucose is low. Several molecular defects are known to cause hyperinsulinism of infancy, such as K(ATP) channelopathies and regulatory defects of glucokinase and glutamate dehydrogenase. Although defects of fatty acid oxidation have not previously been known to cause hyperinsulinism, patients with deficiency in SCHAD (short-chain 3-hydroxyacyl-CoA dehydrogenase; an enzyme of mitochondrial beta-oxidation) have hyperinsulinism. A novel link between fatty acid oxidation and insulin secretion may explain hyperinsulinism in these patients.
Asunto(s)
3-Hidroxiacil-CoA Deshidrogenasas/deficiencia , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Hiperinsulinismo/enzimología , 3-Hidroxiacil-CoA Deshidrogenasas/genética , Animales , Insulina/metabolismo , Secreción de Insulina , MutaciónRESUMEN
A female infant of nonconsanguineous Indian parents presented at 4 months with a hypoglycemic convulsion. Further episodes of hypoketotic hypoglycemia were associated with inappropriately elevated plasma insulin concentrations. However, unlike other children with hyperinsulinism, this patient had a persistently elevated blood spot hydroxybutyrylcarnitine concentration when fed, as well as when fasted. Measurement of the activity of L-3-hydroxyacyl-CoA dehydrogenase in cultured skin fibroblasts with acetoacetyl-CoA substrate showed reduced activity. In fibroblast mitochondria, the activity was less than 5% that of controls. Sequencing of the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) genomic DNA from the fibroblasts showed a homozygous mutation (C773T) changing proline to leucine at amino acid 258. Analysis of blood from the parents showed they were heterozygous for this mutation. Western blot studies showed undetectable levels of immunoreactive SCHAD protein in the child's fibroblasts. Expression studies showed that the P258L enzyme had no catalytic activity. We conclude that C773T is a disease-causing SCHAD mutation. This is the first defect in fatty acid beta-oxidation that has been associated with hyperinsulinism and raises interesting questions about the ways in which changes in fatty acid and ketone body metabolism modulate insulin secretion by the beta cell. The patient's hyperinsulinism was easily controlled with diazoxide and chlorothiazide.
Asunto(s)
3-Hidroxiacil-CoA Deshidrogenasas/deficiencia , 3-Hidroxiacil-CoA Deshidrogenasas/genética , Carnitina/análogos & derivados , Hiperinsulinismo/genética , Hiperinsulinismo/fisiopatología , Insulina/metabolismo , Mutación Puntual , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Carnitina/sangre , Carnitina/química , Cartilla de ADN/genética , Evolución Molecular , Ácidos Grasos/metabolismo , Femenino , Expresión Génica , Homocigoto , Humanos , Hiperinsulinismo/enzimología , Hipoglucemia/enzimología , Hipoglucemia/etiología , Hipoglucemia/fisiopatología , Técnicas In Vitro , Lactante , Secreción de Insulina , Modelos Biológicos , Datos de Secuencia Molecular , Oxidación-Reducción , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homología de Secuencia de AminoácidoRESUMEN
In this study of 118 children (median age 5.1 years; range 6 months to 17 years) with ischaemic stroke or transient ischaemic attack (TIA), 22 children (19%) were homozygous for the thermolabile variant of the methylenetetrahydrofolate reductase allele (t-MTHFR), compared with nine of 78 (12%) of a reference population (p=0.18, OR 1.76, 95% CI 0.76 to 4.04). Of those with cerebrovascular disease (CVD), 17 of 84 were homozygous for the t-MTHFR allele (p=0.13 compared with the reference population (OR 1.95, 95% CI 0.81 to 4.65). There was a significant (p<0.025) increment of plasma total homocysteine concentration in homozygotes for the t-MTHFR allele compared with heterozygotes, negatives for the t-MTHFR allele, and control children with no history of stroke. In four of 12 homozygotes for the t-MTHFR allele, plasma homocysteine levels were raised, compared with three of 38 of those who were negative or heterozygous (p=0.047; OR 5.8, 95% CI 1.1 to 31.2). Homozygotes for the t-MTHFR allele were significantly more likely to have a recurrent event than those who were negative or heterozygous (Cox regression p=0.031, hazard ratio 2.18, 95% CI 1.08 to 4.42). These data suggest that homozygosity for the t-MTHFR allele is associated with raised homocysteine levels in children and is a risk factor for primary and secondary stroke and TIA.
Asunto(s)
Trastornos Cerebrovasculares/genética , Homocisteína/sangre , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/genética , Accidente Cerebrovascular/genética , Adolescente , Alelos , Trastornos Cerebrovasculares/sangre , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Homocigoto , Humanos , Lactante , Ataque Isquémico Transitorio/sangre , Ataque Isquémico Transitorio/genética , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2) , Recurrencia , Factores de Riesgo , Accidente Cerebrovascular/sangre , TemperaturaRESUMEN
We describe three further children with the DOOR syndrome (deafness, onycho-osteodystrophy and mental retardation). A severe seizure disorder and characteristic facial appearance are part of the syndrome. Fourteen similar cases including the present patients are now on record. Autosomal recessive inheritance is likely. An increased level of 2-oxoglutarate in both plasma and urine has been found in our three patients. It is suggested there may be an inherited metabolic defect in this malformation syndrome.
Asunto(s)
Anomalías Múltiples/genética , Huesos/anomalías , Sordera/genética , Discapacidad Intelectual/genética , Ácidos Cetoglutáricos/metabolismo , Anomalías Múltiples/metabolismo , Preescolar , Sordera/metabolismo , Femenino , Genes Recesivos , Humanos , Lactante , Discapacidad Intelectual/metabolismo , Masculino , Uñas Malformadas , Convulsiones/genética , SíndromeRESUMEN
A patient aged 23 months with fructose-1,6-diphosphatase deficiency is reported. This infant demonstrated an increased urine excretion of glycerol-3-phosphate during episodes of hypoglycaemia. The excretion of this compound has not previously been described in this disease or in those disorders associated with a deficiency in one of the other three gluconeogenic enzymes associated with hypoglycaemia. Its presence in the urine from patients may be useful in diagnosis.
Asunto(s)
Errores Innatos del Metabolismo de los Carbohidratos/enzimología , Deficiencia de Fructosa-1,6-Difosfatasa , Glicerofosfatos/orina , Errores Innatos del Metabolismo de los Carbohidratos/orina , Femenino , Humanos , Hipoglucemia/orina , LactanteRESUMEN
1. We have investigated the effects of moderate long-term exercise on protein turnover in fed man by measuring the extent of whole-body nitrogen production, the labelling of urinary ammonia from ingested [15N]glycine and plasma, muscle and urine free amino acid concentrations. 2. Judged both from nitrogen production, and from the extent of 13CO2 production from ingested L-[1-13C]leucine, exercise causes a substantial rise in amino acid catabolism. 3. Amino acids catabolized during exercise appear to become available through a fall in whole-body protein synthesis and a rise in whole-body protein breakdown. After exercise, protein balance becomes positive through a rise in the rate of whole-body synthesis in excess of breakdown. 4. Studies of free 3-methylhistidine in muscle, plasma and urine samples suggest that exercise decreases the fractional rate of myofibrillar protein breakdown, in contrast with the apparent rise in whole-body breakdown.