RESUMO
Seven boys with an apparently X-linked syndrome of dilated cardiomyopathy, growth retardation, neutropenia, and persistently elevated urinary levels of 3-methylglutaconate, 3-methylglutarate, and 2-ethylhydracrylate were studied. The natural history of the disorder was characterized by severe or lethal cardiac disease and recurrent infections during infancy and early childhood but relative improvement in later childhood. The initial presentation of the syndrome varied from congenital dilated cardiomyopathy to infantile congestive heart failure to isolated neutropenia without clinical evidence of heart disease. The excretion of 3-methylglutaconate and 3-methylglutarate appeared to be independent of the metabolism of leucine, the presumed precursor of these organic acids in humans. Although the cause of the organic aciduria remains obscure, the constellation of biochemical and clinical abnormalities forms a distinct syndrome that may be a relatively common cause of dilated cardiomyopathy or neutropenia in boys during infancy and childhood.
Assuntos
Cardiomiopatia Dilatada/genética , Glutaratos/urina , Transtornos do Crescimento/genética , Neutropenia/genética , Cromossomo X , Adulto , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Fumaratos/urina , Transtornos do Crescimento/metabolismo , Insuficiência Cardíaca/genética , Humanos , Masculino , Meglutol/análogos & derivados , Meglutol/urina , Doenças Musculares/genética , Doenças Musculares/patologia , Neutropenia/metabolismo , Neutropenia/patologia , Linhagem , SíndromeRESUMO
The clinical, pathologic, and biochemical features of rhizomelic chondrodysplasia punctata are described in two patients. Although both patients had clinical and radiologic similarities, one patient survived for only 13 days and the other is still alive at 8 years. The most prominent pathologic feature was the marked degenerative change in the chondrocytes from resting cartilage. Fibroblast alkyldihydroxyacetone phosphate synthase activity was markedly reduced in both patients (approximately 10% of control mean); in contrast, dihydroxyacetone phosphate acyltransferase activity was only moderately reduced (50% of control mean). Alkyl and alk-l-enyl ether (plasmalogens) levels were very low in brain and liver. The accumulation of phytanic acid observed in plasma or liver was paralleled by a reduced ability of the patients' fibroblasts to oxidize phytanic acid. Our data indicate that the genetic defect in rhizomelic chondrodysplasia punctata results in abnormalities in two apparently unrelated pathways (i.e., phytanic acid oxidation and ether lipid biosynthesis.
Assuntos
Condrodisplasia Punctata/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Cartilagem/metabolismo , Cartilagem/patologia , Condrodisplasia Punctata/metabolismo , Fibroblastos/metabolismo , Humanos , Recém-Nascido , Metabolismo dos Lipídeos , Fígado/metabolismo , Fígado/patologia , MasculinoRESUMO
Measurement of pyruvate and lactate produced from glucose by confluent skin fibroblast cultures from 95 patients with lactic acidemia revealed 10 in whom the lactate/pyruvate ratio (L/P) was increased (L/P = 57 to 232) compared with that observed in control cell lines (L/P = 18 to 35). Mitochondria prepared from these cells revealed two types of respiratory chain defect. In four patients the deficient activity was present in NADH-coenzyme Q reductase (14% to 21% of controls), and in six the deficiency was in cytochrome c oxidase (21% to 28% of controls). The four patients with NADH-coQ reductase deficiency presented early with lactic acidosis, respiratory failure, anorexia, and hypotonia; all four died within 7 months. The group with cytochrome oxidase deficiency had a somewhat later (18 months to 2 years of age) presentation with milder lactic acidemia, but also with hypotonia and anorexia. They had delayed development, beginning to walk and talk at 18 to 24 months, and then slowly regressed. Although an investigation of central nervous system disorders in this latter group has not been possible, the clinical progression fits into the broad category of Leigh disease. We conclude that in these two groups respiratory chain defects can be detected and localized by the use of skin fibroblast cultures.