Non-invasive functional assessment and pathogenesis of Morquio A

7.项目总结/摘要 粘多糖样沉积症IVA（MPS IVA，Morquio A病）是一种罕见的常染色体隐性遗传病， 溶酶体酶N-乙酰半乳糖胺6-硫酸硫酸酯酶（GALNS）缺乏。GALNS催化 糖胺聚糖的降解：硫酸角质素（KS）和6-硫酸软骨素（C6 S）。MPs IVA 由于KS和C6 S的进行性储存，患者发展成特征性骨骼发育不良。患者 出生时看起来健康，尽管有些患者甚至在出生时就出现异常骨骼发育不良。患者 通常在两年内因短躯干侏儒症，齿状突发育不全， 鸡胸、脊柱后凸、外翻或关节活动过度。具有严重表型的患者通常不会 由于颈部不稳定/狭窄、气管阻塞， 心肺功能受损患者需要多次骨科手术（颈椎减压/融合， 截骨术、髋关节重建和置换术等）在他们的一生中。酶替代疗法 和造血干细胞疗法在临床上是可用的。基因治疗和酶降解底物 治疗正在开发中。在1998年，我们开始向登记处的病人收集医疗资料 数据库该数据库包含约400名患者，并建立了一个增长图表，表明 人口增长明显不佳，人口不平衡，导致公共部门IVA健康状况不佳。然而，由于这些数据 基于对自我完成问卷的答复，数据存在固有的局限性， 解释。目前对MPS IVA患者治疗的临床评估是6分钟步行试验、3分钟步行试验和3分钟步行试验。 爬楼梯试验和强迫肺功能试验。这些耐力测试对小孩子来说很难， 坐轮椅的病人和接受外科手术的病人。用于评估骨骼的方法 发育异常疾病对于患者来说可能是昂贵的、耗时的和令人疲惫的。更好的方法来 评估，包括家庭评估，需要评估临床疗效，并提供最佳的 MPS IVA患者的临床治疗。拟议的项目将评估多个领域的非侵入性， 包括肺功能、骨矿化、步态、关节松弛、气管功能， 听觉功能拟议的非侵入性评估将提供一种有效和创新的方法， 描述疾病的特征并评估治疗的益处，即使是在小型但多样化的患者中 尽管有年龄和身体残疾。我们的诊所已经招募了100多名MPS IVA患者， 使我们的机构成为世界上最受欢迎的网站，非常适合完成这个项目。的 采用非侵入性方法的评估计划将对科学和健康产生重大影响， 详细描述了MPS IVA中主要骨骼问题的进展和发病机制。该项目的成果 还将定义临床终点，以衡量未来临床产品和干预措施的有效性， 适用于其他骨骼发育不良。 1

7. Project Summary/Abstract Mucopolysaccharidosis IVA (MPS IVA, Morquio A Disease) is a rare autosomal recessive disorder caused by a deficiency of the lysosomal enzyme, N-acetylgalactosamine 6-sulfate sulfatase (GALNS). GALNS catalyzes the degradation of the glycosaminoglycans: keratan sulfate (KS) and chondroitin-6-sulfate (C6S). MPS IVA patients develop a characteristic skeletal dysplasia due to the progressive storage of KS and C6S. Patients appear healthy at birth, although some patients present with abnormal skeletal dysplasia even at birth. Patients usually come to medical attention within two years of life because of short trunk dwarfism, odontoid hypoplasia, pectus carinatum, kyphosis, genu valgum, or hypermobile joints. Patients with severe phenotype often do not survive beyond a few decades of life because of cervical instability/stenosis, tracheal obstruction, and cardiopulmonary compromise. Patients require multiple orthopedic surgeries (cervical decompression/fusion, osteotomy, hip reconstruction and replacement, etc.) throughout their lifetime. Enzyme replacement therapy and hematopoietic stem cell therapy are available clinically. Gene therapy and enzyme degradation substrate therapy are under development. In 1998, we began collecting medical information from patients in the Registry Database. The database contains around 400 patients and has established a growth chart that indicates marked poor growth with the imbalance and consequent poor health in MPS IVA. However, since these data are based on responses to a self-completion questionnaire, there are inherent limitations to the data and their interpretation. Current clinical assessments of therapies for MPS IVA patients are a 6-min walk test, a 3-min stair climb test, and forced pulmonary function test. These endurance tests are difficult for small children, patients in wheelchairs, and patients undergoing surgical procedures. Methods used to assess skeletal dysplasia disorders can be expensive, time-consuming, and exhausting for the patients. Better methods for assessment, including in-home evaluations, are needed to evaluate clinical efficacy and to provide optimal clinical treatments for MPS IVA patients. The proposed project will assess multiple domains non-invasively, which includes pulmonary function, bone mineralization, gait pattern, laxity of joints, tracheal function, and hearing function. Proposed non-invasive assessments will provide an effective and innovative way of characterizing the disease and evaluating the benefits of therapies even in small but diverse patient populations despite age and physical handicaps. Over 100 MPS IVA patients have been enrolled in our clinic, making our institution the most popular site in the world and ideally suited to complete this project. The assessment program with non-invasive methods will have a significant impact on science and health by detailing the progression and pathogenesis of major skeletal problems in MPS IVA. The outcome of this project will also define clinical endpoints to measure the efficacy of future clinical products and interventions and may apply to other skeletal dysplasias. 1