Genetic Underpinnings of CM and SM and Effect on Brain Development

项目总结 Chiari I型畸形(CM1)，即小脑通过枕大孔进入脊柱的突出 神经管疾病是最常见的儿科神经系统疾病之一，大约每1000人中就有1人患有此病。 CM1的特点是小脑通过枕大孔进入椎管， 通常导致脊髓空洞症(SM)，椎管内充满液体的囊肿，正常脑脊髓的梗阻 体液流动，脑干受压，以及许多神经症状。我们现在已经确定了一些 CM1的第一个遗传学原因，并已确定特发性巨头症是主要的病因亚型 CM1.通过识别CM1和CM1相关成像生物标记物背后的其他遗传因素，我们希望 发现其他CM1亚型及其遗传基础。此外，我们的目标是了解CM1- 相关的遗传变异，我们已经通过对斑马鱼的特定遗传变异进行建模来识别 确定导致常见结果的系统(脑、脊柱、头骨、脑室系统)受影响 后脑移位。对CM1患者进行更早、更准确的诊断将产生深远的影响， 告知临床决定谁应该接受手术(对比脑脊液分流术还是手术+脊柱手术 聚变与观测等)以及在什么时间范围内。

PROJECT SUMMARY Chiari type I malformation (CM1), the herniation of the cerebellum through the foramen magnum into the spinal canal, is one of the most common pediatric neurological conditions, found in approximately 1 in 1000 individuals. CM1 is characterized by the herniation of the cerebellum through the foramen magnum into the spinal canal, often leading to syringomyelia (SM), a fluid-filled cyst within the spinal canal, obstruction of normal cerebrospinal fluid flow, compression of the brainstem and numerous neurological symptoms. We now have identified some of the first genetic causes of CM1 and have identified idiopathic macrocephaly as a major etiological subtype of CM1. By identifying additional genetic factors underlying CM1 and CM1-related imaging biomarkers, we hope to uncover additional CM1 subtypes and their genetic basis. Additionally, our goal is to understand the role of CM1- associated genetic variation that we have already identified by modeling specific genetic variants in zebrafish to determine what systems are affected (brain, spine, skull, ventricular system) that lead to the common outcome of hindbrain displacement. Earlier and more accurate diagnoses for CM1 patients will have profound effects, informing clinical decisions regarding who should undergo surgery (versus CSF shunting vs surgery+spinal fusion vs observation, etc) and along what time frame.