RESUMO
Disorders of neuronal migration can lead to malformations of the cerebral neocortex that greatly increase the risk of seizures. It remains untested whether malformations caused by disorders in neuronal migration can be reduced by reactivating cellular migration and whether such repair can decrease seizure risk. Here we show, in a rat model of subcortical band heterotopia (SBH) generated by in utero RNA interference of the Dcx gene, that aberrantly positioned neurons can be stimulated to migrate by reexpressing Dcx after birth. Restarting migration in this way both reduces neocortical malformations and restores neuronal patterning. We further find that the capacity to reduce SBH continues into early postnatal development. Moreover, intervention after birth reduces the convulsant-induced seizure threshold to a level similar to that in malformation-free controls. These results suggest that disorders of neuronal migration may be eventually treatable by reengaging developmental programs both to reduce the size of cortical malformations and to reduce seizure risk.
Assuntos
Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Modelos Animais de Doenças , Proteínas Associadas aos Microtúbulos/genética , Neuropeptídeos/genética , Convulsões/genética , Animais , Animais Geneticamente Modificados , Movimento Celular/genética , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/patologia , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/terapia , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/veterinária , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Feminino , Técnicas de Silenciamento de Genes , Predisposição Genética para Doença , Terapia Genética , Malformações do Desenvolvimento Cortical do Grupo II/embriologia , Malformações do Desenvolvimento Cortical do Grupo II/genética , Malformações do Desenvolvimento Cortical do Grupo II/patologia , Malformações do Desenvolvimento Cortical do Grupo II/veterinária , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/fisiologia , Modelos Biológicos , Neurônios/patologia , Neurônios/fisiologia , Neuropeptídeos/antagonistas & inibidores , Neuropeptídeos/fisiologia , Gravidez , Interferência de RNA/fisiologia , Ratos , Convulsões/patologia , Convulsões/terapia , Índice de Gravidade de DoençaRESUMO
INTRODUCTION: Hirschsprung's disease (HD), or aganglionic megacolon, is a congenital disorder that is characterised by the absence of ganglion cells in the submucosal and myenteric plexuses of the intestine, which is caused by the failure of these cells to migrate from the neural crest (neurocristopathy). Cerebral dysgenesis and polymalformation syndromes have been reported in association with HD, thus suggesting an abnormal morphogenesis. AIM: To study the frequency of cerebral malformations in patients with HD in our environment. PATIENTS AND METHODS: We conducted a retrospective study of 41,666 live newborn infants, over the period 1993-2003, and 17 cases of HD where identified. RESULTS: The incidence of HD in the health district of the province of Albacete is 1.68 per 5,000 live newborn infants. Of the 17 patients with HD who were studied, 10 were isolated (58.8%) and seven (41.1%) were associated to other structural abnormalities and psychomotor retardation. Three of the cases in this latter group were due to chromosome pathology (trisomy 21, Down syndrome), two were caused by specific polymalformation syndromes (one Mowat-Wilson syndrome and one possible FG syndrome), one was due to a pattern of abnormalities that did not fit any known syndrome, and one had a normal phenotype and isolated cerebral dysgenesis. In all of cases the neuroimaging studies identified cerebral dysgenesis that was compatible with neuronal migration disorders. CONCLUSIONS: The frequency of association of HD, either isolated or within the context of a specific malformation syndrome, with neuronal migration disorders is high (23.5%). We suggest a full genetic and neurological evaluation should be carried out in patients with HD, together with brain imaging studies in order to rule out the possibility of cerebral dysgenesis.
