A Two-Year Observation on the Efficacy and Safety of Enzyme Replacement Therapy in a Fabry Disease Pedigree: A Single-Center Case Series Report
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摘要:
目的 评估酶替代治疗（enzymereplacementtherapy，ERT）在携带c.167G>A突变的法布里病（fabry disease，FD）家系中的2年疗效与安全性。 方法 回顾性分析2022年09月至2024年10月云南地区1个携带c.167G>A （p.Cys56Tyr）突变的FD家系4例患者的临床资料，旨在通过对比治疗前及治疗 2 年后血浆α-半乳糖苷酶A活性（α-GalA）、脱乙酰基三己糖酰基鞘脂醇水平（Lyso-GL-3）及心、肝、肾功能相关参数、Mainz 严重程度评分指数（mainz severity score index，MSSI）及健康调查简表（36-item short form health survey，SF-36）评分综合评价疗效。 结果 经ERT后，生物标志物血浆Lyso-GL-3水平与α-GalA活性分别下降62.6%、27.9%。心脏参数左室后壁厚度（left ventricular posterior wall thickness，LVPWT）、左室质量指数（left ventricular mass index，LVMI）、心衰标志物（n-terminal pro b-type natriuretic peptide，NT-proBNP）（降低，射血分数（left ventricular ejection fraction，LVEF）改善；肝肾功能指标维持稳定；MSSI总分显著降低，SF-36各维度评分显著升高，表明患者疾病严重程度减轻且生活质量提高。1例患者出现下肢水肿，经对症治疗后缓解，未发生严重不良事件。 结论 ERT可有效降低携带c.167G>A突变的FD家系患者血浆Lyso-GL-3水平，改善临床症状。 Abstract:Objective To assess the two-year efficacy and safety of enzyme replacement therapy （ERT） in a Fabry disease （FD） pedigree carrying the c.167G>A mutation. Methods Clinical data of four patients from a FD pedigree carrying the c.167G>A （p.Cys56Tyr） mutation in Yunnan province, between September 2022 and October 2024 were retrospectively analyzed. A comprehensive efficacy assessment was performed by comparing plasmaα-galactosidase A （α-GalA） activity, lyso-globotriaosylsphingosine （Lyso-GL-3） levels, cardiac/hepatic/renal function indices, Mainz Severity Score Index （MSSI）, and 36-Item Short Form Health Survey （SF-36） scores before and after two years of ERT. Results Following ERT, plasma Lyso-GL-3 levels and α-GalA activity decreased by 62.6% and 27.9%, respectively. Cardiac parameters showed improvement: left ventricular posterior wall thickness （LVPWT）, left ventricular mass index （LVMI） and the heart failure marker N-terminal pro-B-type natriuretic peptide （NT-proBNP） decreased, while left ventricular ejection fraction （LVEF） improved. Hepatic and renal function indices remained stable. The total MSSI score significantly decreased, and all domain scores of the SF-36 significantly increased, indicating reduced disease severity and enhanced quality of life. One patient experienced lower limb edema, which resolved with symptomatic treatment; with no serious adverse events reported. Conclusion ERT effectively reduces plasma Lyso-GL-3 levels and improve clinical symptoms in FD pedigree patients carrying the c.167G>A mutation. -
Key words:
- Fabry disease /
- Enzyme replacement therapy /
- Efficacy /
- Safety
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图 2 ERT前后血Lyso-GL-3[μmol/（L·h）]含量比较
Figure 2. Comparison of plasma Lyso-GL-3 levels before and after ERT
图 3 ERT前后LVMI（g/m2）变化比较
Figure 3. Comparison of left ventricular mass index （LVMI） changes before and after ERT
图 4 ERT前后Ccr（mL/min）变化比较
Figure 4. Comparison of creatinine clearance rate （Ccr） changes before and after ERT
表 1 4例患者的基本信息及临床资料
Table 1. Baseline information and clinical characteristics of the four patients
各项指标 III1 III3 III5 III10 性别 女 女 女 男 ERT治疗的年龄（岁） 60 57 54 51 诊断指标 a-GalA[μmol/（L·h）] 1.56 1.63 1.67 0.73 Lyso-GL-3（ng/mL） 16.89 9.27 6.23 47.10 GLA基因突变 + + + + 病理活检 - - - - 临床症状 周围神经性疼痛 + + + + 少汗症/无汗症 + - - - 皮肤血管角质瘤 - - - - 角膜涡状浑浊 - - - - 视力下降 - - - - 听力下降 - - - + 胃肠功能障碍 + + + + 呼吸功能障碍 + - + + 肾功能障碍 + + - + 心肌肥厚 + + + + 脑卒中 + + + + 分型 经典型 迟发型 迟发型 经典型 注：α-GaLA：参考范围：2.40～17.65[μmol/（L·h）]；Lyso-GL-3：参考范围：<1.11ng/mL，“+”表示有，“-”表示无。 
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表 2 4例法布里患者酶替代治疗前后a-GalA活性和Lyso-GL-3水平变化
Table 2. Changes in α-GalA activity and Lyso-GL-3 levels in the four FD patients before and after ERT
各项指标 III1 III3 III5 III10 $ \bar x \pm s $ Lyso-GL-3[μmol/（L·h）] 治疗前 16.89 9.27 6.23 47.10 19.87 ± 18.70 治疗后 6.82 6.15 4.77 11.97 7.43 ± 3.15 a-GalA（ng/mL） 治疗前 1.56 1.63 1.67 0.73 1.40 ± 0.45 治疗后 0.88 1.39 1.36 0.42 1.01 ± 0.46
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表 3 4例患者心脏彩超参数及心脏标记物变化情况
Table 3. Changes in cardiac colordoppler ultrasound parameters and cardiac biomarkers in the four Patients
各项指标 III1 III3 III5 III10 $ \bar x \pm s $ LAD（mm） 用药前 30 34 25 44 33.25 ± 8.06 用药后 33 37 24 43 34.25 ± 7.97 IVST（mm） 用药前 11 10 8 15 11.00 ± 2.94 用药后 12 10 9 14 11.25 ± 2.22 LVPWT（mm） 用药前 13 10.7 9 16 12.18 ± 3.03 用药后 13 13 8 13 11.75 ± 2.50 LVDD（mm） 用药前 46 48 43 53 47.50 ± 4.20 用药后 43 47 47 55 48.00 ± 5.03 LVEF（%） 用药前 66 56 65 54 60.25 ± 6.13 用药后 62 65 71 53 62.75 ± 7.50 LVMI（g/m2） 用药前 131.38 128.05 79.81 197.71 134.23 ± 48.43 用药后 121.66 138.76 89.47 165.18 128.76 ± 31.73 hs-cTnT（μg/L） 用药前 0.278 0.043 0.016 0.129 0.12 ± 0.12 用药后 0.315 0.040 0.018 0.129 0.13 ± 0.14 NT-proBNP（pg/mL） 用药前 1947 6613 586.5 20394 7385.13 ±9048.42 用药后 2058 3760 406 16214 5609.50 ±7201.06
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表 4 4例患者酶替代治疗后肝肾功能相关指标变化情况比较
Table 4. Comparison of hepatic and renal function-related indicators in the four patients before and after ERT
各项指标 III1 III3 III5 III10 $ \bar x \pm s $ CREA（μmol/L） 用药前 71 67 79 967 296.00 ± 447.36 用药后 82 80 83 794 259.75 ± 356.17 ACR（mg/mmol） 用药前 4.18 7.25 1.36 无尿 4.26 ± 2.95 用药后 89.61 295.6 14.69 无尿 133.30 ± 145.46 Ccr（mL/min） 用药前 68.76 63.84 58.82 7.40 49.70 ± 28.49 用药后 54.36 51.55 55.74 10.5 43.04 ± 21.76 UTP（mg/24 h） 用药前 210 480 326.8 无尿 338.93 ± 135.40 用药后 207 518.4 140.4 无尿 288.60 ± 201.78 ALT（U/L） 用药前 12 53 19 7 20.76 ± 10.38 用药后 29 25 23 10 21.75 ± 8.22 AST（U/L） 用药前 20 60 20 4 26.00 ± 23.89 用药后 40 35 33 15 30.75 ± 10.90
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表 5 4例患者酶替代治疗前后MSSI评分变化情况
Table 5. Changes in Mainz severity score index （MSSI） scores in the four patients before and after ERT
各项指标 III1 III3 III5 III10 $ \bar x \pm s $ 一般情况 用药前 9 7 7 9 8.00 ± 1.15 用药后 4 4 4 5 4.25 ± 0.50 肾脏系统 用药前 8 8 8 8 8.00 ± 0.00 用药后 8 4 8 18 9.50 ± 5.97 心血管系统 用药前 11 11 11 16 12.25 ± 2.50 用药后 11 11 11 11 11.00 ± 0.00 神经系统 用药前 13 11 9 15 12.00 ± 2.58 用药后 3 3 3 6 3.75 ± 1.50 总分 用药前 41 37 35 48 40.25 ± 0.74 用药后 26 22 26 40 28.50 ± 7.90
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表 6 4例患者酶替代治疗前后SF-36评分变化情况
Table 6. Changes in 36-item short form health survey （SF-36） scores in the four patients before and after ERT
各项评分 III1 III3 III5 III10 $ \bar x \pm s $ 生理机能 用药前 25 45 75 55 50.00 ± 20.82 用药后 35 55 85 75 62.50 ± 22.17 生理职能 用药前 0 0 0 0 0.00 ± 0.00 用药后 0 0 50 100 37.50 ± 47.87 躯体疼痛 用药前 12 22 41 41 29.00 ± 14.45 用药后 31 74 74 41 55.00 ± 22.32 一般健康状况 用药前 20 15 40 25 25.00 ± 10.80 用药后 45 57 50 62 53.50 ± 7.50 精力 用药前 20 30 30 50 32.50 ± 12.58 用药后 20 55 65 60 47.50 ± 19.36 社会功能 用药前 37.5 12.5 62.5 62.5 43.75 ± 23.94 用药后 62.5 62.5 87.5 87.5 75.00 ± 14.43 情感职能 用药前 0 0 0 33.3 8.33 ± 16.65 用药后 0 0 100 100 50.00 ± 57.74 精神健康 用药前 24 44 28 52 37.00 ± 13.22 用药后 48 80 72 68 67.00 ± 13.61 健康变化 用药前 25 50 50 25 37.50 ± 14.43 用药后 100 100 75 100 93.75 ± 12.50
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