5例法布里病患者临床表现、基因变异及酶替代疗法效果分析

Clinical features,genetic variations and enzyme replacement therapy in five Chinese patients with Fabry disease

目的分析酶替代疗法治疗法布里病(Fabry disease)的有效性和安全性。方法回顾性收集和分析2020年7月至2021年5月期间浙江大学医学院附属第一医院收治的5例法布里病患者的临床资料、基因检测及家系调查结果、酶替代治疗效果和不良反应。5例患者阿加糖酶β用量为1 mg·kg^(-1)·次^(-1)静脉泵注,每2周用药1次。结果5例患者均为男性,中位年龄37岁(29~51岁),均通过结合临床表现、家族史、肾病理检查、α⁃半乳糖苷酶A(α⁃Gal A)活性检测及基因检测结果明确诊断。临床表现多样,所有患者均有尿检异常及心电图和心脏B超异常,肾功能不全4例,幼年时肢端疼痛3例(持续至成年1例),皮肤血管角化瘤3例,少汗4例,腹泻4例,角膜涡状混浊4例,高频听力异常2例。基因测序结果显示,2例为GLA基因错义变异[c.272T>C(p.I91T),c.868A>G(p.Met290Val)],1例为移码突变[c.348del p.(Ile117Phefs*4)],2例为无义突变[c.1024C>T(p.Arg342*),c.838C>T(p.Gln280*)],其中移码突变患者表现为经典型法布里病,该变异在已知数据库中未见收录。5例患者输注阿加糖酶β过程中均未发生严重不良反应。酶替代治疗2~10个月后,5例患者血浆三己糖酰基鞘脂醇(Lyso⁃GL⁃3)水平较治疗前显著下降(P<0.05),4例患者长期腹泻症状在用药后明显改善。结论法布里病临床表现和基因变异多样,短期阿加糖酶β治疗未见严重不良反应,治疗后患者血浆Lyso⁃GL⁃3水平显著下降。

Objective To analyze the efficacy and safety of enzyme replacement therapy(ERT)in Chinese patients with Fabry disease.Methods A retrospective analysis of the clinical manifestations,genetic variations,family screening,treatments and adverse reactions was conducted in five patients with Fabry disease admitted to the First Affiliated Hospital of Zhejiang University College of Medicine from July 2020 to May 2021.The dosage of agalsidaseβwas 1 mg/kg by intravenous pump once every 2 weeks.Results Five male patients with median age of 37 years old(29-51 years old)were diagnosed based on clinical features,family history,α⁃galactosidase A(α⁃Gal A)activity,genetic analysis results and kidney biopsy.The clinical manifestations varied in these five patients.All patients had abnormal electrocardiogram,abnormal cardiac ultrasonography and abnormal urinalysis results,three experienced acroparaesthesia during childhood(one patient had persistent pain until adulthood),three had cutaneous angiokeratoma,four had renal insufficiency,four had hypohidrosis,four had diarrheas,four had cornea verticillata and two had high⁃frequency hearing loss.Two missense mutations of the GLA gene were identified:c.272T>C(p.I91T)and c.868A>G(p.Met290Val).Two nonsense mutations were c.1024C>T(p.Arg342*)and c.838C>T(p.Gln280*).Furthermore,the frameshift mutation c.348del p.(Ile117Phefs*4)was detected,which was not included in the known database,presented with classical Fabry disease.There was no serious adverse reaction during agalsidaseβinfusion in 5 patients.ERT reduced the plasma globotriaosylsphingosine(lyso⁃GL⁃3)levels after treatment of 2^(-1)0 months(P<0.05),and the long⁃term diarrhea symptom were significantly improved.Conclusions The clinical manifestations of Fabry disease are varied.Severe adverse events rarely occur in patients treated with short⁃term ERT.Plasma lyso⁃GL⁃3 levels decrease significantly after treatment.