RESUMO
Fetal-onset hydrocephalus (HC), which affects between 1:500 and 1:5000 live human births, results from unequal production and drainage of cerebrospinal fluid (CSF) and is associated with abnormal development of the cerebral cortex leading to severe neurological deficits. We previously found that in the hydrocephalic Texas rat, the CSF of affected fetuses induced a cell cycle arrest in neural progenitor cells. Here, we show that alterations in folate metabolism in the CSF of the developing cerebrum are likely responsible for this effect. We identified 3 folate enzymes in the CSF and demonstrate that low levels of one of these, 10-formyltetrahydrofolate dehydrogenase, are associated with HC in the hydrocephalic Texas rat. Therefore, we tested whether supplementation with specific folate species would improve developmental outcome. After daily administration of a combination of tetrahydrofolic and 5-formyltetrahydrofolic acids to pregnant dams, there was a significant reduction in the incidence of HC and improved brain development. By contrast, supplementation with folic acid increased the incidence of congenital HC in this model. These results indicate the complexities of folate metabolism in the developing brain and suggest that folate imbalance leading to HC in the hydrocephalic Texas rat fetuses can be treated with maternal folate supplementation using specific folate metabolites and combinations thereof.
Assuntos
Ácido Fólico/líquido cefalorraquidiano , Hidrocefalia/líquido cefalorraquidiano , Hidrocefalia/prevenção & controle , Fatores Etários , Animais , Bromodesoxiuridina/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/embriologia , Córtex Cerebral/patologia , Líquido Cefalorraquidiano/química , Líquido Cefalorraquidiano/metabolismo , Distribuição de Qui-Quadrado , Modelos Animais de Doenças , Combinação de Medicamentos , Embrião de Mamíferos , Feminino , Hidrocefalia/embriologia , Hidrocefalia/patologia , Leucovorina/administração & dosagem , Troca Materno-Fetal/efeitos dos fármacos , Gravidez , Ratos , Ratos Mutantes , Ratos Sprague-Dawley , Células-Tronco/efeitos dos fármacos , Tetra-Hidrofolatos/administração & dosagem , Complexo Vitamínico B/administração & dosagemRESUMO
Five novel mutations have been identified in the gene encoding L1CAM, a neural cell adhesion protein, in families with X linked hydrocephalus (XHC). Interestingly, all five mutations are in the evolutionarily highly conserved Ig-like domains of the protein. The two frameshift mutations (52insC and 955delG) and the nonsense mutation (Trp276Ter) most probably result in functional null alleles and complete absence of L1CAM at the cell surface. The two missense mutations (Tyr194Cys and Pro240Leu) may considerably alter the structure of the L1CAM protein. These data provide convincing evidence that XHC is genetically extremely heterogeneous.