The Natural History of Autosomal Dominant Osteopetrosis Type 2

摘要NIAMS自然Hx提案 摘要 常染色体显性骨硬化症2型（ADO 2）是一种罕见的骨质疏松症， 由于氯离子通道7基因突变引起的骨吸收， 显性负性机制外显率约为66%，疾病严重程度差异很大。影响 个体通常具有至少一种显著的临床表现，包括骨折，骨坏死， 骨髓炎失明或骨髓衰竭我们的10名患者已经死亡（超过80例临床 临床表现），或者是疾病表现，或者是严重疾病的治疗尝试。自然 ADO 2中疾病表现的进展尚不清楚，尽管有限的数据表明该疾病 越老越糟虽然目前没有有效的治疗方法，但动物模型的研究表明， 产生有希望的数据和人体试验即将到来。因此，必须了解 ADO 2的自然史，包括可靠的生物标志物和相关的以患者为中心的结局， 衡量疗效，指导临床试验设计。自然历史研究将 建立系列表型受试者队列，以获取临床重要结局并表征 疾病严重程度、疾病进展和当前或未来疾病的新生物标志物的变化 严重性。本研究的目的是1）确定临床相关的生物学（临床，生化， 密度测定或放射学）和患者报告的结局，以及2）确定ADO 2的自然史， 包括疾病进展的速度。我们将着重于以下具体目标： 具体目标1：确定临床试验的疾病严重程度和终点的关键标志物。 A.完善并验证复合临床严重程度分级量表。 A.将我们先前研究中的联合收割机样本和测量结果与 参与受试者确定哪些临床、生物学、放射学和密度测定终点最佳 定义当前疾病的严重程度并预测未来疾病的严重程度和结果。 B。检验ADO 2疾病严重程度随年龄增长而恶化的假设。 C.比较上述研究中3种最常见突变患者的测量结果 在我们的激酶（G215 R，R286 W和R767 W），以确定基因型-表型相关性，以及是否 单个突变预测疾病的严重程度。 具体目标2：建立电子ADO 2患者登记系统，收集基于人群的纵向 生活质量，疼痛，残疾和其他基于调查的数据，从任何个人与骨硬化症。此注册表 将作为参与上述研究目标的受试者的数据存储库，将提供长期的 后续数据继续超过完成这项赠款，并成为一个潜在的持续来源 未来新疗法的临床试验招募。

Abstract NIAMS Natural Hx Proposal Abstract Autosomal dominant osteopetrosis type 2 (ADO2) is a rare osteosclerotic disorder resulting from impaired osteoclastic bone resorption due to mutations in the Chloride Channel 7 gene, which cause disease by a dominant negative mechanism. Penetrance is approximately 66% and disease severity varies widely. Affected individuals typically have at least one significant clinical manifestation including fractures, osteonecrosis, osteomyelitis, blindness, or bone marrow failure. Ten of our patients have died (out of >80 with clinical manifestations) either of disease manifestations or from attempts at therapy for severe disease. The natural progression of disease manifestations in ADO2 is unknown, although limited data suggests that the disease gets worse with age. Although no effective therapy is currently available, studies in animal models have generated promising data and human trials on are on the horizon. Therefore, it is imperative to understand the natural history of ADO2, including reliable biological markers and relevant patient centered outcomes, to measure therapeutic effect, and to guide the design of clinical trials. The proposed natural history study will establish a cohort of serially phenotyped subjects to capture clinically important outcomes and characterize variations in disease severity, progression of disease, and novel biomarkers for current or future disease severity. The goals of this study are to 1) identify clinically relevant biological (clinical, biochemical, densitometric, or radiographic) and patient-reported outcomes and 2) determine the natural history of ADO2, including the rate of disease progression. We will focus on the following specific aims: Specific Aim 1: Determine key markers of disease severity and endpoints for a clinical trial. A. Refine and validate a composite clinical severity grading scale. A. Combine samples and measurements from our prior studies with prospectice serial measurements in participating subjects to determine which clinical, biological, radiological, and densitometric endpoints best define current disease severity and predict future disease severity and outcomes. B. Test the hypothesis that ADO2 disease severity gets worse with age. C. Compare measures obtained in the studies outlined above in patients with the 3 most common mutations in our kindreds (G215R, R286W, and R767W) to identify genotype-phenotype correlations, and whether the individual mutations predict disease severity. Specific Aim 2: Establish an electronic ADO2 patient registry, which will collect population-based, longitudinal quality-of-life, pain, disability and other survey-based data from any individual with osteopetrosis. This registry will serve as a data repository for subjects participating in the research aims above, will provide long-term follow-up data continuing beyond the completion of this grant, and be an ongoing source of potential recruitment to future clinical trials of novel therapies.