Asunto(s)
Condrodisplasia Punctata Rizomélica/genética , Condrodisplasia Punctata Rizomélica/mortalidad , Niño , Preescolar , Condrodisplasia Punctata Rizomélica/diagnóstico por imagen , Condrodisplasia Punctata Rizomélica/patología , Femenino , Humanos , Lactante , Recién Nacido , Morbilidad , Embarazo , Ultrasonografía PrenatalRESUMEN
Rhizomelic chondrodysplasia punctata is a human autosomal recessive disorder characterized by skeletal, eye and brain abnormalities. The disorder is caused by mutations in the PEX7 gene, which encodes the receptor for a class of peroxisomal matrix enzymes. We describe the generation and characterization of a Pex7 mouse knockout (Pex7(-/-)). Pex7(-/-) mice are born severely hypotonic and have a growth impairment. Mortality in Pex7(-/-) mice is highest in the perinatal period although some Pex7(-/-) mice survived beyond 18 months. Biochemically Pex7(-/-) mice display the abnormalities related to a Pex7 deficiency, i.e. a severe depletion of plasmalogens, impaired alpha-oxidation of phytanic acid and impaired beta-oxidation of very-long-chain fatty acids. In the intermediate zone of the developing cerebral cortex Pex7(-/-) mice have an increase in neuronal density. In vivo neuronal birthdating revealed that Pex7(-/-) mice have a delay in neuronal migration. Analysis of bone ossification in newborn Pex7(-/-) mice revealed a defect in ossification of distal bone elements of the limbs as well as parts of the skull and vertebrae. These findings demonstrate that Pex7 knockout mice provide an important model to study the role of peroxisomal functioning in the pathogenesis of the human disorder.
Asunto(s)
Movimiento Celular , Condrodisplasia Punctata Rizomélica/genética , Neuronas/metabolismo , Osteogénesis , Receptores Citoplasmáticos y Nucleares/genética , Acetil-CoA C-Acetiltransferasa/biosíntesis , Animales , Animales Recién Nacidos , Encéfalo/enzimología , Células Cultivadas , Condrodisplasia Punctata Rizomélica/mortalidad , Condrodisplasia Punctata Rizomélica/patología , Dieta , Fibroblastos/citología , Fibroblastos/metabolismo , Marcación de Gen , Hígado/enzimología , Ratones , Ratones Noqueados , Mutación , Osteoblastos/ultraestructura , Osteoclastos/ultraestructura , Oxidación-Reducción , Receptor de la Señal 2 de Direccionamiento al Peroxisoma , Peroxisomas/metabolismo , Ácido Fitánico/metabolismo , Fitol/metabolismo , Plasmalógenos/biosíntesis , Receptores Citoplasmáticos y Nucleares/deficiencia , Factores de TiempoRESUMEN
Rhizomelic chondrodysplasia punctata (RCP) is a rare autosomal recessive disorder with many associated medical complications. Prior to this study, natural history information about RCP was limited and based on experiences with small populations of affected individuals. We delineate the natural history of RCP through systematic analysis of 35 previously unreported individuals (as well as review of 62 literature cases with respect to survival and cause of death). Survival, growth, and developmental expectations and medical needs are summarized based upon experience with this population. Survival is greater among this population than previously reported, with 90% surviving up to 1 year and 50% surviving up to 6 years. Cause of death is most often respiratory problem. All infants with RCP have joint contractures, bilateral cataracts, and severe growth and psychomotor delays. Recommendations for health supervision of children with RCP and for parental counseling are presented.