Lysosomal Disorders Unit, Institute of Immunity and Transplantation, Royal Free London NHS Foundation Trust, University College of London, London, United Kingdom.
Nephrology Service, Research Center, Hôpital du Sacré-Coeur de Montréal and University of Montreal, Montreal, QC, Canada.
Mol Genet Metab. 2019 May;127(1):86-94. doi: 10.1016/j.ymgme.2019.03.010. Epub 2019 Apr 3.
Fabry disease is a rare, X-linked, lifelong progressive lysosomal storage disorder. Severely deficient α-galactosidase A activity in males is associated with the classic phenotype with early-onset, multisystem manifestations evolving to vital organ complications during adulthood. We assessed the ability of 2 low-dose agalsidase beta regimens to lower skin, plasma, and urine globotriaosylceramide (GL-3) levels, and influence clinical manifestations in male pediatric Fabry patients.
In this multicenter, open-label, parallel-group, phase 3b study, male patients aged 5-18 years were randomized to receive agalsidase beta at 0.5 mg/kg 2-weekly (n = 16) or 1.0 mg/kg 4-weekly (n = 15) for 5 years. All had plasma/urine GL-3 accumulation but no clinically evident organ involvement. The primary outcome was GL-3 accumulation in superficial skin capillary endothelium (SSCE).
The mean age was 11.6 (range: 5-18) years and all but one of the 31 patients had classic GLA mutations. In the overall cohort, shifts from non-0 to 0-scores for SSCE GL-3 were significant at years 1, 3, and 5, but results were variable. Plasma GL-3 normalized and urine GL-3 reduced substantially. Higher anti-agalsidase beta antibody titers were associated with less robust SSCE GL-3 clearance and higher urine GL-3 levels. Renal function remained stable and normal. Most Fabry signs and symptoms tended to stabilize; abdominal pain was significantly reduced (-26.3%; P = .0215). No new clinical major organ complications were observed. GL-3 accumulation and cellular and vascular injury were present in baseline kidney biopsies (n = 7). Treatment effects on podocyte GL-3 content and foot process width were highly variable. Fabry arteriopathy overall increased in severity. Two patients withdrew and 2 had their agalsidase beta dose increased.
Our findings increase the limited amount of available data on long-term effects of enzyme replacement therapy in pediatric, classic Fabry patients. The low-dose regimens studied here over a period of 5 years did not demonstrate a consistent benefit among the patients in terms of controlling symptomatology, urine GL-3 levels, and pathological histology. The current available evidence supports treatment of pediatric, classic male Fabry patients at the approved agalsidase beta dose of 1.0 mg/kg 2-weekly if these patients are considered for enzyme replacement therapy with agalsidase beta.
法布里病是一种罕见的 X 连锁、终身进行性溶酶体贮积症。男性中 α-半乳糖苷酶 A 活性严重缺乏与经典表型相关，其特征为早期发病、多系统表现，在成年期发展为重要器官并发症。我们评估了两种低剂量阿加糖酶β治疗方案降低皮肤、血浆和尿液神经节苷脂（GL-3）水平的能力，并影响男性儿科法布里病患者的临床表现。
在这项多中心、开放标签、平行组、3b 期研究中，年龄为 5-18 岁的男性患者被随机分配接受阿加糖酶β 0.5mg/kg，每 2 周 1 次（n=16）或 1.0mg/kg，每 4 周 1 次（n=15），治疗 5 年。所有患者均有血浆/尿液 GL-3 堆积，但无明显的器官受累。主要结局是皮肤浅层毛细血管内皮（SSCE）中 GL-3 的堆积。
平均年龄为 11.6 岁（范围：5-18 岁），31 名患者中除 1 名外均有经典 GLA 突变。在整个队列中，SSCE GL-3 从非 0 分变为 0 分的变化在第 1、3 和 5 年时具有统计学意义，但结果存在差异。血浆 GL-3 正常化，尿液 GL-3 显著减少。较高的抗阿加糖酶β抗体滴度与 SSCE GL-3 清除率较低和尿液 GL-3 水平较高相关。肾功能保持稳定和正常。大多数法布里病的体征和症状趋于稳定；腹痛显著减少（-26.3%；P=.0215）。未观察到新的临床主要器官并发症。在基线肾脏活检（n=7）中发现 GL-3 堆积和细胞及血管损伤。治疗对足细胞 GL-3 含量和足突宽度的影响高度可变。法布里血管病的严重程度总体增加。2 名患者退出，2 名患者增加了阿加糖酶β剂量。
我们的研究结果增加了在儿科经典法布里病患者中酶替代治疗长期效果的有限数据。在 5 年的研究期间，我们研究的低剂量方案并未显示出治疗方案在控制症状、尿液 GL-3 水平和病理组织学方面对患者有一致的益处。目前的证据支持对儿科经典型男性法布里病患者进行阿加糖酶β治疗，治疗剂量为 1.0mg/kg，每 2 周 1 次，如果这些患者考虑进行阿加糖酶β酶替代治疗。
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