Abstract：
Pathogenic variants in the Cu/Zn superoxide dismutase (SOD1) gene can be detected in approximately 2% of sporadic and 11% of familial amyotrophic lateral sclerosis (ALS) patients in Europe. We analyzed the clinical phenotypes of 83 SOD1-ALS patients focusing on patients carrying the most frequent (likely) pathogenic variants (R116G, D91A, L145F) in Germany. Moreover, we describe the effect of tofersen treatment on ten patients carrying these variants. R116G patients showed the most aggressive course of disease with a median survival of 22.0 months compared to 198.0 months in D91A and 87.0 months in L145F patients (HR 7.71, 95% CI 2.89-20.58 vs. D91A; p < 0.001 and HR 4.25, 95% CI 1.55-11.67 vs. L145F; p = 0.02). Moreover, R116G patients had the fastest median ALSFRS-R progression rate with 0.12 (IQR 0.07-0.20) points lost per month. Median diagnostic delay was 10.0 months (IQR 5.5-11.5) and therefore shorter compared to 57.5 months (IQR 14.0-83.0) in D91A (p < 0.001) and 21.5 months (IQR 5.8-38.8) in L145F (p = 0.21) carriers. As opposed to D91A carriers (50.0%), 96.2% of R116G (p < 0.001) and 100.0% of L145F (p = 0.04) patients reported a positive family history. During tofersen treatment, all patients showed a reduction of neurofilament light chain (NfL) serum levels, independent of the SOD1 variant. Patients with SOD1-ALS carrying R116G, D91A, or L145F variants show commonalities, but also differences in their clinical phenotype, including a faster progression rate with shorter survival in R116G, and a comparatively benign disease course in D91A carriers.
摘要：
在欧洲，大约2％的散发性和11％的家族性肌萎缩性侧索硬化症（ALS）患者中可以检测到Cu/Zn超氧化物歧化酶（SOD1）基因的致病变体。我们分析了83例SOD1-ALS患者的临床表型，重点是携带最常见（可能）致病变异的患者（R116G，D91A,L145F）在德国。此外，我们描述了tofersen治疗对10名携带这些变异的患者的影响。R116G患者表现出最积极的病程，与D91A的198.0个月和L145F患者的87.0个月相比，中位生存期为22.0个月（HR7.71，95％CI2.89-20.58vs.D91A；p<0.001和HR4.25，95%CI1.55-11.67vs.L145F;p=0.02)。此外，R116G患者的中位ALSFRS-R进展率最快，每月损失0.12（IQR0.07-0.20）分。中位诊断延迟为10.0个月（IQR5.5-11.5），因此与D91A（p<0.001）的57.5个月（IQR14.0-83.0）和L145F（p=0.21）携带者的21.5个月（IQR5.8-38.8）相比更短。与D91A载波(50.0%)相反，96.2%的R116G(p<0.001)和100.0%的L145F(p=0.04)患者报告有阳性家族史。在托费森治疗期间，所有患者均显示神经丝轻链（NfL）血清水平降低，独立于SOD1变体。携带R116G的SOD1-ALS患者，D91A,或L145F变体显示共性，但它们的临床表型也有差异，包括R116G的更快的进展速度和更短的生存期，D91A携带者的病程相对良性。
