背景:庞贝氏症,一种由酸性α-葡萄糖苷酶缺乏引起的罕见常染色体隐性遗传疾病,导致进行性糖原积累和多系统功能障碍。重组人酸性α-葡萄糖苷酶的酶替代疗法是标准的治疗方法;然而,一些患者产生抗重组人酸性α-葡萄糖苷酶抗体,导致疗效降低。该病例报告介绍了两名患有早发性庞贝氏症的婴儿,他们产生了针对酶替代疗法的IgG抗体,随后接受了甲氨蝶呤治疗。强调监测抗体开发和探索替代治疗方法的重要性。
方法:患者1,来自波哥大的10个月大女性,哥伦比亚,表现为广泛性张力减退,巨舌,反射减退,和轻度左心室肥厚.诊断测试证实了早发性庞皮病,酶替代疗法在12个月时开始.由于缺乏改进和高抗重组人酸性α-葡萄糖苷酶IgG抗体滴度(1:1800),甲氨蝶呤开始于18个月。经过8个月的综合治疗,抗体滴度为阴性,使用粗大运动功能测量88观察到运动功能显著改善.病人2,一名来自波哥大的7岁女性,哥伦比亚,在12个月时被诊断为早发性Pompe病,并开始了酶替代疗法。在5岁的时候,她经历了频繁的跌倒和握力改变。功能测试显示电机发育延迟,广泛性低张力,和阳性的抗重组人酸性α-葡萄糖苷酶IgG抗体滴度(6400)。开始使用甲氨蝶呤,导致6个月后跌倒和抗体滴度(3200)降低,无不良事件或并发症。使用运动功能测量32评估运动功能改善。
结论:这些病例强调了在酶替代疗法期间监测患者抗重组人酸性α-葡萄糖苷酶抗体发展的重要性,以及甲氨蝶呤作为免疫调节剂在早发性庞贝氏症中的潜在益处。早期诊断并及时启动酶替代疗法,结合预防性免疫耐受诱导,可以改善临床结果并减少抗重组人酸性α-葡萄糖苷酶抗体的发展。这些案例还强调了客观运动功能评估工具的重要性,例如粗大运动功能测量88和运动功能测量32,用于评估治疗反应。需要进一步的研究来优化治疗方案,监测长期影响,并解决了Pompe病中酶替代疗法的当前局限性。
BACKGROUND: Pompe disease, a rare autosomal recessive disorder caused by acid alpha-glucosidase deficiency, results in progressive glycogen accumulation and multisystem dysfunction. Enzyme replacement therapy with recombinant human acid alpha-glucosidase is the standard of care; however, some patients develop anti-recombinant human acid alpha-glucosidase antibodies, leading to reduced efficacy. This case report presents two infants with early-onset Pompe disease who developed IgG antibodies to enzyme replacement therapy and were subsequently treated with methotrexate, highlighting the importance of monitoring antibody development and exploring alternative therapeutic approaches.
METHODS: Patient 1, a 10-month-old female from Bogota, Colombia, presented with generalized hypotonia, macroglossia, hyporeflexia, and mild left ventricular hypertrophy. Diagnostic tests confirmed early-onset Pompe disease, and enzyme replacement therapy was started at 12 months. Due to a lack of improvement and high anti-recombinant human acid alpha-glucosidase IgG antibody titers (1:1800), methotrexate was started at 18 months. After 8 months of combined therapy, antibody titers were negative and significant improvement in motor function was observed using the Gross Motor Function Measure 88. Patient 2, a 7-year-old female from Bogota, Colombia, was diagnosed with early-onset Pompe disease at 12 months and initiated enzyme replacement therapy. At 5 years of age, she experienced frequent falls and grip strength alterations. Functional tests revealed motor development delay, generalized hypotonia, and positive anti-recombinant human acid alpha-glucosidase IgG antibody titers (6400). Methotrexate was initiated, leading to a reduction in falls and antibody titers (3200) after 6 months, with no adverse events or complications. Motor function improvement was assessed using the Motor Function Measurement 32.
CONCLUSIONS: The presented cases highlight the importance of monitoring patients for anti-recombinant human acid alpha-glucosidase antibody development during enzyme replacement therapy and the potential benefit of methotrexate as an immunomodulatory agent in early-onset Pompe disease. Early diagnosis and timely initiation of enzyme replacement therapy, combined with prophylactic immune tolerance induction, may improve clinical outcomes and reduce the development of anti-recombinant human acid alpha-glucosidase antibodies. The cases also highlight the importance of objective motor function assessment tools, such as Gross Motor Function Measure 88 and Motor Function Measurement 32, in assessing treatment response. Further research is needed to optimize treatment regimens, monitor long-term effects, and address the current limitations of enzyme replacement therapy in Pompe disease.