Integrated Longitudinal Studies to Identify Biomarkers and Therapeutic Strategies for Sturge-Weber Syndrome

斯特奇-韦伯综合征(SWS)是一种皮肤、眼和脑血管毛细血管疾病 血管瘤导致鲜红斑斑的血管瘤影响皮肤，血管瘤和青光眼 眼部，以及脑部周围的软脑膜血管瘤。2013年，脑血管成员 畸形协会(BVMC)共同鉴定了GNAQ基因中的一个体细胞激活突变 (编码G阿尔法亚单位)。这种突变发生在胎儿时期 发展，因此，即使在早期诊断，血管畸形已经存在 而且可能是不可逆转的。然而，与许多脑血管病变一样，严重的并发症 可由血管畸形和周围脑实质的影响引起。 最近，斯特奇-韦伯基金会(SWF)将患者和临床医生聚集在一起 确定患者未得到满足的需求。而神经症状包括癫痫和 头痛是常见的中风样发作、严重的癫痫发作和偏头痛。 被认为会显著影响患者的生活质量。目前用于预防这些疾病的治疗方法 症状包括阿司匹林和癫痫药物，但这两种药物都没有得到纵向的很好支持。 学习。目前也不清楚是什么导致了中风样症状，也不清楚如何识别SWS患者 有出现这些症状的风险。我们上一次资助期间的精美系列脑成像研究 提供了重要的线索显示血管结构本身的变化以及 周围的脑实质，包括密集的脑钙化，可能是这些 症状。因此，另一种可能令人兴奋的治疗方法是通过一种 改变用途的毒品。在这里，我们将通过 确定高危患者，分析当前的治疗方法，并确定稳健的， 临床上有用的和可预测的生物标志物。 我们计划扩展我们的患者登记数据，以整合纵向临床、放射和 患者的血液生物标记物，以确定那些最有可能出现严重神经症状的人 并确定可能的治疗方法(目标1)。我们将确定将发生变化的成像生物标记物 随着时间的推移，并与严重的神经症状相关(目标2)。最后，对于登记的患者 出现严重神经症状的人，将对血浆样本进行筛查 严重症状发生时、期间和之后的炎症变化以确定预测性 临床试验的生物标记物(目标3)。一个主要的交付成果将是临床上有用的、综合的 纵向数据库和仪表板工具，帮助可视化数据，帮助临床医生更好地 了解SWS突变后的病程进展。

Sturge-Weber Syndrome (SWS) is a skin, eye, and brain vascular disorder of capillary angiomas resulting in port wine stain angiomas affecting the skin, angiomas and glaucoma of the eye, and leptomeningeal angiomas surrounding the brain. In 2013, members of the Brain Vascular Malformations Consortium (BVMC) co-identified a somatic, activating mutation in the GNAQ gene (which encodes the G alpha subunit) in affected vascular tissue. This mutation occurs during fetal development and thus, even with early diagnosis, the vascular malformation is already present and may not be reversible. However, as with many vascular brain lesions, serious complications can arise from the effects of the vascular malformation and the surrounding brain parenchyma. Recently, the Sturge-Weber Foundation (SWF) brought together patients and clinicians to identify unmet needs for patients. While neurological symptoms including seizures and headaches are common, stroke-like episodes, severe bouts of seizures, and migraine headaches were felt to significantly impact patient quality of life. Current treatments used to prevent these symptoms include aspirin and seizure medications, but neither is well supported by longitudinal studies. Nor is it clear exactly what causes stroke-like symptoms or how to identify SWS patients at risk for these symptoms. Elegant serial brain imaging studies from our previous grant period have provided important clues showing changes in the vascular structures themselves as well as surrounding brain parenchyma, including dense brain calcifications that could underlie these symptoms. Hence, another potentially exciting treatment is to target brain calcifications through a repurposed drug. Here, we will address pressing needs for clinical trial readiness through the identification of at risk patients, analysis of current treatments, and identification of robust, clinically useful and predictive biomarkers. We plan to extend our patient registry data to integrate longitudinal clinical, radiological, and blood biomarkers of patients to identify those at most risk to have severe neurological symptoms and to identify potential treatments (Aim 1). We will identify imaging biomarkers that will change over time and correlate with severe neurological symptoms (Aim 2). Finally, for enrolled patients who present with severe neurological symptoms, plasma samples will be screened for inflammatory changes at baseline, during, and after the severe symptoms to identify predictive biomarkers for clinical trials (Aim 3). A major deliverable will be a clinically useful, integrated longitudinal database and dashboard tool to help visualize data that will help clinicians better understand progression of disease course following the SWS mutation.