Ries Markus, Clarke Joe T R, Whybra Catharina, Timmons Margaret, Robinson Chevalia, Schlaggar Bradley L, Pastores Gregory, Lien Y Howard, Kampmann Christoph, Brady Roscoe O, Beck Michael, Schiffmann Raphael
Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1260, USA.
Pediatrics. 2006 Sep;118(3):924-32. doi: 10.1542/peds.2005-2895.
Fabry disease is an X-linked multisystem disorder. Enzyme-replacement therapy in adults has limited efficacy in treating major sequelae of advanced Fabry disease, such as kidney failure or stroke. This prompted a study of the safety and efficacy of enzyme replacement at an earlier stage of Fabry disease.
Our purpose with this work was to evaluate safety and to explore efficacy of enzyme treatment with agalsidase alfa in pediatric patients with Fabry disease.
We conducted a 6-month open-label study at 3 tertiary care centers with 24 children (19 boys and 5 girls) with a mean age of 11.8 (range: 6.5-18) years, to examine safety parameters, including infusion reactions and antiagalsidase alfa antibodies.
Agalsidase alfa was well tolerated, and all of the patients completed the study. Six boys and 1 girl had mild-to-moderate infusion reactions. One boy developed transient immunoglobulin G antibodies against agalsidase alfa. The boys showed a significant reduction in plasma globotriaosylceramide on treatment. Mean estimated glomerular filtration rate, cardiac structure, and function were normal and did not change over 26 weeks. Heart rate variability, as determined by 2-hour ambulatory monitoring, was decreased in the boys compared with the girls at baseline. All indices of heart rate variability improved significantly in the boys. Three patients with anhidrosis, as determined by quantitative sudomotor axon reflex testing, developed sweating. Six of 11 patients could reduce or cease their use of antineuropathic analgesics.
Enzyme replacement with agalsidase alfa was safe in this study. The exploratory efficacy analysis documented increased clearance of globotriaosylceramide and improvement of autonomic function. Prospective long-term studies are needed to assess whether enzyme replacement initiated early in patients with Fabry disease is able to prevent major organ failure in adulthood.
法布里病是一种X连锁多系统疾病。成人的酶替代疗法在治疗晚期法布里病的主要后遗症（如肾衰竭或中风）方面疗效有限。这促使人们在法布里病的早期阶段研究酶替代疗法的安全性和有效性。
我们开展这项研究的目的是评估阿加糖酶α酶替代治疗法布里病儿科患者的安全性，并探索其疗效。
我们在3家三级医疗中心进行了一项为期6个月的开放标签研究，纳入24名儿童（19名男孩和5名女孩），平均年龄为11.8岁（范围：6.5 - 18岁），以检查安全性参数，包括输液反应和抗阿加糖酶α抗体。
阿加糖酶α耐受性良好，所有患者均完成了研究。6名男孩和1名女孩出现了轻度至中度输液反应。1名男孩产生了针对阿加糖酶α的短暂免疫球蛋白G抗体。治疗后男孩的血浆球三糖神经酰胺显著降低。平均估计肾小球滤过率、心脏结构和功能正常，在26周内未发生变化。通过2小时动态监测确定，男孩的心率变异性在基线时低于女孩。男孩的所有心率变异性指标均有显著改善。通过定量汗腺轴突反射测试确定的3例无汗患者出现了出汗。11例患者中有6例可以减少或停止使用抗神经病理性镇痛药。
在本研究中，阿加糖酶α酶替代治疗是安全的。探索性疗效分析表明，球三糖神经酰胺清除增加，自主神经功能得到改善。需要进行前瞻性长期研究，以评估法布里病患者早期开始酶替代治疗是否能够预防成年期的主要器官衰竭。
