AN OPEN - LABEL EXTENSION STUDY OF PATIENTS WITH LATE-ONSET POMPE DISEASE

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 9/18/2007 庞贝氏症是一种罕见的常染色体隐性遗传性代谢性肌肉疾病，由酸缺乏引起。葡萄糖苷酶（GAA），一种降解溶酶体糖原的酶。从历史上看，庞贝氏症已被任意分为不同的亚型的基础上发病的年龄症状，器官参与的程度，并进展到死亡率。基本上，疾病的范围很广，从快速进展型（发作性）到更缓慢进展型（晚发性），在这些极端之间存在相当大的变异性和重叠（Chen，2000，Mol Med Today;赫什霍恩，2001，The Metabolic and Molecular Bases of Inherited Disease;货车den Hout，2003，Pediatrics）。重要的是要注意，庞贝氏症的所有表现都有一个共同的潜在病理学;即，GAA缺乏，随后糖原积累。 在疾病谱中进展最快的一端是患有庞贝氏症的发作形式的患者。这些患者通常在第一次出现症状时出现症状。 12个月的生命。糖原在心脏和骨骼肌中的大量沉积导致快速进展的心肌病和全身性肌无力和肌张力减退。此外，运动发育通常完全停滞，或者即使达到运动里程碑，它们随后也会丢失。心脏和/或呼吸衰竭导致的死亡通常发生在大多数患者1岁之前（赫什霍恩，2001，The Metabolic and Molecular Bases of Inherited Disease）。在文献中，这种典型病程的患者被描述为“经典”的战斗型庞贝氏症。Slonim及其同事已经描述了存活超过1年的一个亚组的顽固性庞贝氏症患者（Slonim，2000，J Pediatr）。这些患者的临床病程特征为心肌病进展较慢和生存期较长，患者通常在1至2岁之间发生呼吸衰竭。虽然有些患者在1岁之前死亡，但其他患者可能存活超过2年。 迟发性庞贝氏症的进展速度不如初发性庞贝氏症。症状出现在儿童时期或晚至60岁。患者表现为进行性肌病，主要发生在骨盆和肩胛带的近端肌肉，并伴有呼吸系统受累的可变进展。通常，这些患者发生最小程度的心肌病或不发生心肌病（Chen，2000，Mol Med Today; Lafor t，2000，Neurology;赫什霍恩， 2001，遗传疾病的代谢和分子基础）。晚发性病程 庞贝氏症比婴儿型更难预测，一些患者经历骨骼和呼吸肌功能的快速恶化，导致截肢和呼吸衰竭，其他患者进展较慢，还有一些患者在骨骼和呼吸肌功能恶化的进展中分离，导致截肢和呼吸衰竭，其他患者进展较慢，还有一些在骨骼肌和呼吸肌受累的进展中出现分离（Lafor t，2000，Neurology）。 最后，大多数患者坐轮椅，需要呼吸机支持，最终死于呼吸衰竭（Chen，2000，Mol Med Today; Hirshhorn，2001，The Metabolic and Molecular Bases of Inherited Disease）。 Genzyme Corporation生产了重组形式的人酸性α-葡糖苷酶（rhGAA）Myozyme，一种用于庞贝氏症的研究性酶替代疗法（ERT）。 希望ERT能够恢复溶酶体GAA活性，消耗蓄积的溶酶体糖原，并防止底物进一步蓄积。rhGaa由编码GAA的互补脱氧核糖核酸（cDNA）稳定表达的中国仓鼠卵巢细胞生产。 婴儿型临床试验目前已停止招募。目前，新诊断的婴儿型患者可根据Genzyme的扩大使用计划接受ERT治疗。晚发型前瞻性观察性研究（LOPOS）开始于2004年，也完全招募了58名轻度至中度晚发型庞贝氏症患者。开始对晚发型患者的临床试验具有重要意义。 假设： 本研究旨在评价美而赞在晚发型庞贝氏症患者中的安全性和疗效。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 9/18/2007 Pompe disease is a rare autosomal recessive metabolic muscle disease caused by the deficiency of acid ? glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Historically, Pompe disease has been arbitrarily classified into different subtypes based on the age at onset of symptoms, extent of organ involvement, and rate of progression to death. Essentially, there is a broad spectrum of disease ranging from a rapidly progressive form (infantile-onset) to a more slowly progressive form (late-onset) with considerable variability and overlap existing between these extremes (Chen, 2000, Mol Med Today; Hirschhorn, 2001, The Metabolic and Molecular Bases of Inherited Disease; van den Hout, 2003, Pediatrics). It is important to note that all presentations of Pompe disease share a common underlying pathology; i.e., deficiency of GAA with subsequent accumulation of glycogen. At the most rapidly progressive end of the disease spectrum are patients with the infantile-onset form of Pompe disease. These patients typically present with symptoms within the first 12 months of life. A massive deposition of glycogen in the heart and skeletal muscle results in rapidly progressive cardiomyopathy and generalized muscle weakness and hypotonia. Moreover, motor development is often completely arrested, or if motor milestones are achieved, they are subsequently lost. Death from cardiac and/or respiratory failure generally occurs before most patients reach 1 year of age (Hirschhorn, 2001, The Metabolic and Molecular Bases of Inherited Disease). Patients presenting with this typical disease course have been described in the literature as having 'classical' infantile-onset Pompe disease. A subset of patients with infantile-onset Pompe disease that survive beyond 1 year has been described by Slonim and colleagues (Slonim, 2000, J Pediatr). The clinical course of disease in these patients is characterized by a slower progression of cardiomyopathy and longer survival, with patients generally developing respiratory failure between 1 and 2 years of age. Although some patients die before 1 year of age, others may survive beyond 2 years. The late-onset form of Pompe disease progresses less rapidly than the infantile-onset form. Symptoms appear during childhood or as late as the sixth decade of life. Patients present with progressive myopathy, predominantly of the proximal muscles in the pelvic and shoulder girdles, and a variable progression of respiratory involvement. Typically these patients develop minimal or no cardiomyopathy (Chen, 2000, Mol Med Today; Lafor¿t, 2000, Neurology; Hirschhorn, 2001, The Metabolic and Molecular Bases of Inherited Disease). The course of late-onset Pompe disease is less predictable than the infantile form, with some patients experiencing a rapid deterioration in skeletal and respiratory muscle function leading to loss of ambulation and respiratory failure, others progressing less rapidly, and yet others with dissociation in the progression of skeletal and respiratory deterioration in skeletal and respiratory muscle function leading to loss of ambulation and respiratory failure, others progressing less rapidly, and yet others with dissociation in the progression of skeletal and respiratory muscle involvement (Lafor¿t, 2000, Neurology). Eventually, most patients become wheelchair-bound, require ventilator support and ultimately succumb to respiratory failure (Chen, 2000, Mol Med Today; Hirshhorn, 2001, The Metabolic and Molecular Bases of Inherited Disease). Genzyme Corporation has manufactured a recombinant form of human acid alpha-glucosidase, (rhGAA), Myozyme, an investigational enzyme replacement therapy (ERT) for Pompe disease. It is hoped that ERT will restore lysosomal GAA activity, deplete accumulated lysosomal glycogen, and prevent further substrate accumulation. The rhGaa is produced from Chinese hamster ovary cells into which the complementary deoxyribonucleic acid (cDNA) coding for GAA has been stably expressed. Clinical trials for infantile onset form are currently closed to enrollment. At the present time, newly diagnosed infantile onset patients may receive ERT under the expanded access program by Genzyme. Late-onset Prospective Observational Study (LOPOS) began in 2004 and is also fully enrolled with 58 individuals with mild to intermediate late-onset Pompe Disease. It is of much importance to begin the clinical trails on late-onset patients. Hypothesis: The present study intends to evaluate the safety and efficacy of Myozyme in patients with late-onset Pompe disease.