Non-invasive functional assessment and pathogenesis of Morquio A

7.项目摘要/摘要 粘多糖病IVA(MPS IVA，Morquio A病)是一种罕见的常染色体隐性遗传病，由 溶酶体酶N-乙酰氨基半乳糖6-硫酸酯酶(GALNS)缺乏。GALNS催化 糖胺多糖的降解：硫酸角蛋白(KS)和软骨素-6-硫酸酯(C6S)。MPS IVA 由于KS和C6S的进行性储存，患者发展为特征性的骨骼发育不良。病人 出生时看起来很健康，尽管一些患者在出生时就出现了异常的骨骼发育不良。病人 通常在两年内因躯干矮小，齿状突发育不全， 隆胸，后凸，膝外翻，或活动过度的关节。表型严重的患者通常不会 因颈椎不稳/狭窄、气管梗阻而活过几十年 心肺妥协。患者需要多次矫形手术(颈椎减压/融合术， 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 而造血干细胞疗法在临床上是可行的。基因治疗与酶降解底物 治疗方法正在开发中。在1998年，我们开始收集登记处病人的医疗资料 数据库。该数据库包含大约400名患者，并建立了一张增长图表，表明 MPS IVA明显增长不良，不平衡，健康状况不佳。然而，由于这些数据 是基于对自我完成调查问卷的回答，数据和他们的 释义。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 楼梯爬坡试验和用力肺功能试验。这些耐力测试对小孩子来说很难， 坐在轮椅上的病人和正在接受手术的病人。用于评估骨骼的方法 不典型增生疾病对患者来说可能是昂贵的、耗时的和令人精疲力竭的。更好的方法 需要评估，包括家庭评估，以评估临床疗效并提供最佳 MPS静脉血栓形成患者的临床治疗。拟议的项目将非侵入性地评估多个域， 包括肺功能、骨矿化、步态模式、关节松弛、气管功能和 听力功能。提议的非侵入性评估将提供一种有效和创新的方式 描述疾病特征并评估治疗的益处，即使是在小但多样化的患者中也是如此 尽管有年龄和身体残疾，但人口数量仍然很多。我们诊所已经登记了100多名MPS静脉血栓形成患者， 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。这个 使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 详细阐述了MPS IVA中主要骨骼问题的进展和发病机制。这个项目的结果是 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，并可能 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