1 MG/KG BIWEEKLY FABRAZYME ON GASTROINTESTINAL SYMPTOMS OF FABRY DISEASE

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。胃肠道（GI）症状是法布里病的一种常见但未被充分认识的表现，法布里病是一种罕见的X连锁溶酶体贮积症，由酶α-半乳糖苷酶A（α-Gal A）缺乏引起。胃肠道症状通常开始于青春期，并随年龄增长而恶化，50-90%的男性患者报告了胃肠道症状。典型受影响的男性平均寿命为50年;在肾透析和移植可用之前的早期系列中，平均寿命为40年。 典型法布里病的临床表现开始于幼儿期，包括胃肠道症状和其他症状。最常见的症状是腹泻和/或便秘。其他症状包括恶心、呕吐、腹痛、早饱、餐后腹胀和食物不耐受。一般来说，与女性相比，男性的症状更频繁，出现的时间更早。大多数GI症状被认为是GL-3在血管内皮细胞和周皮细胞以及小的无髓鞘神经元和神经束膜细胞的细胞质中蓄积的结果。在接受钡灌肠的一些患者中，已经报告了降结肠和乙状结肠段中结肠吸器的平滑或缺乏;胃排空延迟已经在一定程度上用甲氧氯普胺成功地治疗;小肠和结肠活检显示GL 3在Meissner神经丛的营养神经元、小血管（毛细血管、小静脉和小动脉）和平滑肌细胞中蓄积。 在酶替代疗法（ERT）可用之前，法布里病的唯一治疗选择是姑息性和非特异性的。2003年，在成功完成临床试验后，半乳糖苷酶β（Fabrazyme，Genzyme Corporation，剑桥MA）在美国上市，该临床试验显示GL-3在经典法布里病患者的血浆、肾脏、肝脏、心脏和皮肤中大量清除。 假设：法布里病患者在出生前开始蓄积GL-3;因此，可能需要多年的治疗来减少或消除前几十年未接受治疗的影响。胃肠道症状可对法布里病患者的生活质量产生重大影响。因此，半乳糖苷酶β临床试验的主要终点是证明主要病理器官中GL-3蓄积减少，这一指标被认为与未来临床获益相关。然而，结果表明，胃肠道症状的解决可能是ERT的早期临床获益。

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. Gastrointestinal (GI) symptoms are a common but under-recognized manifestation of Fabry disease, a rare, X-linked lysosomal storage disorder resulting from deficiency of enzyme alpha-galactosidase A (alpha-Gal A). Gastrointestinal symptoms, which typically begin in adolescence and worsen with age, are reported by 50-90% of male patients. Classically affected males have an average lifespan of 50 years; in an earlier series before renal dialysis and transplantation were available, average lifespan was 40 years. Clinical manifestations of classic Fabry disease begin in early childhood and include gastrointestinal symptoms, among other symptoms. The most common symptoms are diarrhea and/or constipation. Other symptoms include nausea, vomiting, abdominal pain, early satiety, post-prandial bloating, and food intolerance. Generally, symptoms are more frequent and appear earlier in life in males as compared to females. Most GI symptoms are believed to be the result of GL-3 accumulation in vascular endothelial and perithelial cells and in the cytoplasm of the small unmyelinated neurons and perineurial cells. Smoothing or lack of colonic haustrae in descending and sigmoid colon segments have been reported in some patients who underwent barium enema; delayed gastric emptying has been successfully treated symptomatically to some extent with metoclopramide; small intestine and colon biopsies have shown GL3 accumulation in vegetative neurons of Meissner plexus, small vessels (capillaries, venules and arterioles) and smooth muscle cells. Before the availability of enzyme replacement therapy (ERT), the only treatment options for Fabry disease were palliative and non-specific. In 2003, agalsidase beta (Fabrazyme, Genzyme Corporation, Cambridge MA) became available in the United States, after successful completion of clinical trials showing substantial clearance of GL-3 in plasma, kidney, liver, heart, and skin in patients with classical Fabry disease. Hypothesis: Patients with Fabry disease begin accumulating GL-3 before birth; thus, years of treatment may be necessary to diminish or undo the effects of prior decades without treatment. Gastrointestinal symptoms can have a significant impact on quality of life for patients with Fabry disease. Thus, the major endpoints of clinical trials of agalsidase beta has been demonstration of decreased GL-3 accumulation in the primary organs of pathology, a measure thought to correlate with future clinical benefit. However, the results suggest that resolution of gastrointestinal symptoms could be an early clinical benefit of ERT.