Exencefalia: diagnóstico prenatal y reporte de caso / Exencephaly: prenatal diagnosis and case report

Resumen La exencefalia es una malformación fetal, donde restos de materia encefálica se encuentran afuera de la bóveda craneal. Las malformaciones congénitas constituyen un problema de salud en nuestro país, la tasa de malformaciones es del orden del 2 al 6% de los recién nacidos. Las malformaciones del sistema nervioso central ocupan el segundo lugar en población de México. Al igual que la mayoría de las malformaciones congénitas, las del sistema nervioso central son un grupo de afecciones de etiología multifactorial, producto de una interacción de factores genéticos, infecciosos, ambientales, raciales, agentes físicos y químicos, y la deficiencia o alteración en el metabolismo del ácido fólico. Se presenta un caso de exencefalia, así como una revisión de la embriología de esta entidad, con énfasis en la importancia del uso del ácido fólico en la etapa de embriogénesis del sistema nervioso central, así como la importancia del abordaje prenatal.

Abstract Exencephaly is a type of cephalic disorder, where the brain is located outside of the skull. Congenital malformations constitute a public health problem in Mexico, affecting approximately 2-6% of newborns. Central nervous system malformations are the second most frequent malformations in the population of Mexico. As with most congenital malformations, the etiology of central nervous system anomalies is multifactorial, resulting from interactions among genetic, infectious, environmental, racial, physical and chemical factors, and deficiency or alteration of folic acid metabolism. We also review the embryology of this entity, with emphasis of the importance of folic acid intake at the stage of central nervous system embryogenesis, and also the importance of the prenatal care.

Secuencia disrrafia-exencefalia-anencefalia asociado a brida amniótica, Síndrome de Klinefelter y polihidramnios / Dysraphia-exencephaly-anencephaly sequence associated with amniotic band, Klinefelter syndrome and polyhydramnios

Los defectos del tubo neural son un grupo heterogéneo y complejo de anomalías del sistema nervioso central que se encuentran entre las anormalidades congénitas humanas más frecuentes, sólo superados por los defectos cardiovasculares, excluyendo las alteraciones cromosómicas. Se caracteriza por ser el resultado final de una anomalía progresiva que se inicia con un disrrafismo del neuroporo rostral por un defecto mesenquimal, seguido de una segunda fase de exposición de hemisferios cerebrales bien diferenciados desarrollado fuera del cráneo embrionario concluyendo con una fase de desintegración. Puede presentarse como evento único o asociado a otras malformaciones. Reportamos tres casos de secuencia disrrafia-exencefalia-anencefalia, uno de ellos en presencia de polihidramnios, otro asociado a síndrome de brida amniótica y otro cuyo estudio cromosómico reporta síndrome de Klinefelter, todos con un resultado común, mal pronóstico perinatal.

Neural tube defects are a complex of central nervous system abnormalities that are among the most common human congenital abnormalities, second only to cardiovascular defects, excluding chromosomal abnormalities and heterogeneous group. It is characterized as the end result of a progressive anomaly that starts with a dysraphism the rostral neuropore by a mesenchymal defect, followed by a second phase exhibit distinct cerebral hemispheres developed beyond the embryonic skull concluding with a phase of disintegration. It can occur as a single event or associated with other malformations. We report three cases of anencephaly -exencephaly-dysraphism sequence, one of them in the presence of polyhydramnios, other associated amniotic band syndrome and other chromosomal study reports Klinefelter syndrome, all with a common result, poor perinatal outcome.

RIC-8B, uma GEF de sistema olfatório, é essencial para o desenvolvimento do sistema nervoso / RIC-8B, an olfactory GEF, is essential for the development of the nervous system

RIC-8B é um fator trocador de nucleotídeo de guanina (GEF) predominantemente expresso em neurônios olfatórios maduros de camundongos adultos. Trabalhos desenvolvidos em nosso laboratório mostraram que RIC-8B interage com Gαolf e Gγ13, duas subunidades de proteína G que estão enriquecidas nos cílios dos neurônios olfatórios, onde participam da transdução do sinal de odorantes. In vitro, RIC-8B é capaz de amplificar a sinalização de receptores olfatórios através de Gαolf, no entanto, seu papel fisiológico ainda é desconhecido. Para determinar a função desempenhada por essa proteína in vivo, nós utilizamos a tecnologia de Gene Trap com o objetivo de produzir um camundongo knockout para Ric-8B. Apesar de a expressão de Ric-8B ser restrita a poucos tecidos no camundongo adulto, descobrimos que homozigotos para a mutação em Ric-8B são inviáveis e morrem por volta do dia embrionário E10,5. Além disso, são menores e apresentam evidente falha no fechamento do tubo neural na região cranial (exencefalia). Utilizamos o gene repórter ß-galactosidase expresso pelo alelo mutado para determinar o padrão de expressão de Ric-8B em embriões durante o desenvolvimento. Observamos que, no estágio E8,5, Ric-8B é expresso nas pregas neurais da região cefálica e na notocorda. De E9,5 a E12,5, a expressão de Ric-8B é detectada predominante no assoalho da placa. Esse padrão de expressão se assemelha ao de outro gene importante para a embriogênese, Sonic hedgehog (Shh). SHH é um morfógeno diretamente responsável pela padronização dorsoventral do sistema nervoso central e sua sinalização depende de cílio primário. Cílio primário é uma organela baseada em microtúbulos que se projeta da superfície da maioria das células de mamíferos e funciona como um centro de sinalização intracelular. Nossos dados mostram que fibroblastos embrionários Ric-8B-/- formam cílios primários, assim como alguns tecidos do embrião. Além disso, não encontramos alterações na sinalização de Shh em embriões homozigotos mutantes. No entanto, observamos que esses embriões apresentam apoptose aumentada em células migratórias da crista neural cranial. Shh é importante para a sobrevivência de células da crista neural migratória, sugerindo um possível papel para Ric-8B a downstream da sinalização de SHH

Ric-8B is a guanine nucleotide exchange factor (GEF) which is predominantly expressed in mature olfactory sensory neurons in adult mice. We have previously shown that RIC-8B interacts with both Gαolf and Gγ13, two G protein subunits, which are enriched in olfactory cilia and are required for odorant signal transduction. In vitro, RIC-8B is able to amplify odorant receptor signaling through Gαolf, however, its physiological role remains unknown. To determine the role played by RIC-8B in vivo we used the Gene trap technology to generate a Ric-8B knockout mouse. We found that, despite the limited distribution of Ric-8B gene expression in adult mice, Ric-8B homozygous mutants are not viable and die around the E10,5 stage. Mutant embryos are also smaller and fail to close the neural tube at the cranial region (exencephaly). We used the activity of the ß-galactosidase reporter gene to determine the pattern of expression of the Ric-8B gene in heterozygous embryos. At E8,5 the Ric-8B gene is expressed in the notochord and neural folds of the cephalic regions. From E9,5 to E12,5 Ric-8B is predominantly expressed in the floor plate, in a pattern that strongly resembles the one shown by Sonic hedgehog (Shh). SHH is a morphogen directly responsible for the dorsoventral patterning of the central nervous system and its signaling depends on primary cilia. Primary cilia are microtubule-based organelles that protrude from the surface of mammalian cells and act as a signaling center. We show that Ric-8B-/- embryonic fibroblasts and some embryonic tissues grow primary cilia normally. In addition, we did not find alterations in the SHH signaling of homozygous mutants. Instead, we found an increased apopotosis in migratory cells of the cranial neural crest in these embryos. Shh is an important factor to survival of neural crest cells, suggesting a role for RIC-8B downstream of the SHH signaling

Experimental exencephaly and myeloschisis in rats

To elucidate the early sequential morphogenetic progress of exencephaly and myeloschisis, rat embryos whose mothers had been treated with hypervitaminosis A were studied at 1-day interval from gestation day 10.5 to 15.5. In exposed animals sequential change was found in both exencephaly and myeloschisis as the embryos grew up. The 10.5-day old exencephalic embryos had still widely open cephalic neural tubes. Exencephalic embryos older than 13.5 days of gestation showed strikingly severe eversion and overgrowth of the cephalic neuroepithelium, thus failed in forming normal primitive brain. The convex dorsal surface of the exencephaly was covered with ependyma, which was connected directly with surrounding surface eqithelium at the periphery. The earliest morphologically recognized myeloschisis was in the 13.5-day old embryos. In myeloschisis, divergence at the roof plate and eversion of the spinal neural tube, disorganized overgrowth of the neuroepithelium, malformed and misplaced spinal ganglia and nerve roots, and absence of the neural arch and dermal covering were characteristic. It is suggested that exencephaly results from failure of the cephalic neural tube closure which is followed by eversion and overgrowth of the neuroepithelium. And failure in closure of the posterior neuropore and disturbance in the development of the tail bud probably play major role in the morphogenesis of myeloschisis.