RESUMO
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.
Assuntos
Carnitina Aciltransferases/deficiência , Erros Inatos do Metabolismo Lipídico/diagnóstico , Mitocôndrias/enzimologia , Morte Súbita do Lactente/diagnóstico , Adulto , Âmnio/citologia , Âmnio/enzimologia , Aleitamento Materno , Carnitina/uso terapêutico , Carnitina Aciltransferases/genética , Carnitina O-Palmitoiltransferase/metabolismo , Córion/citologia , Córion/enzimologia , Diagnóstico Diferencial , Jejum , Evolução Fatal , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos/metabolismo , Fígado Gorduroso/diagnóstico , Feminino , Doenças Fetais/diagnóstico , Fibroblastos/enzimologia , Genes Recessivos , Humanos , Recém-Nascido , Nefropatias/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Leite Humano/química , Doenças Musculares/diagnóstico , Oxirredução , Palmitoilcarnitina/metabolismo , Gravidez , Diagnóstico Pré-Natal , Pele/enzimologia , Pele/patologia , Estresse Fisiológico/metabolismo , Estresse Fisiológico/fisiopatologia , Triglicerídeos/análiseRESUMO
The relative importance of endogenous metabolism and urinary metabolite excretion was assessed in vivo in six children with methylmalonic acidemia by examining the kinetics of the immediate precursor to methylmalonate, propionate. Total production and oxidation of propionate were measured by means of a continuous infusion of (1-13C)propionate and were compared with the urinary excretion of propionate metabolites. Propionate oxidation was substantial (mean 48.9 mumol/kg/hr +/- SD 18.0) and, in four children, exceeded urinary metabolite excretion (mean urinary excretion in all subjects 40 mumol/kg/hr +/- 25). The sum of urinary excretion and oxidation rates (88 mumol/kg/hr +/- 29) approximated the total propionate production (93.4 +/- 37.0), suggesting that these routes together constitute the major mechanisms of propionate disposal. These results suggest that propionate oxidation is an important route of disposal in methylmalonic acidemia. Variations in the relative proportions of propionate disposal through oxidation and urinary excretion may be one reason for the often poor correlation between clinical status and urinary metabolite excretion. Measurement of urinary metabolite concentration alone may not always reflect clinical status and responses to treatment accurately.
Assuntos
Malonatos/metabolismo , Erros Inatos do Metabolismo/metabolismo , Ácido Metilmalônico/metabolismo , Propionatos/farmacocinética , Humanos , Lactente , Recém-Nascido , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/urina , Ácido Metilmalônico/sangue , Ácido Metilmalônico/urina , OxirreduçãoAssuntos
Ácidos Carboxílicos/urina , Doenças em Gêmeos , Hipoglicemia/complicações , Síndrome de Reye/complicações , Cromatografia Gasosa , Diarreia/complicações , Diarreia/urina , Humanos , Hipoglicemia/urina , Lactente , Insulina/sangue , Masculino , Síndrome de Reye/urina , Vômito/complicações , Vômito/urinaRESUMO
Twin male infant siblings who presented in Harrow, UK, with a Reye's-like syndrome associated with profound hypoglycaemia, vomiting, diarrhoea, coma and death in one child, with dicarboxylic aciduria, and similarities to Jamacian vomiting sickness (hypoglycin toxicity) have been shown to excrete large amounts of a previously unrecorded urinary organic acid. This has been identified as 5-hydroxyhexanoic acid by gas chromatography mass spectrometry using a synthesized standard. Concentrations observed were 340 and 330 mg g-1 creatinine in the two patients. The metabolic precursor of the urinary acid is suggested to be hex-4-enoic acid, a probable chemical toxin closely related to the active organic acid metabolite of hypoglycin. The possibility of omega - 1 oxidation of hexanoic acid to 5-hydroxyhexanoic acid in these and other patients with dicarbocylic aciduris is also discussed.