发现与SOD1突变相关的肌萎缩侧索硬化症（SOD1-ALS）的独特特征和发展轨迹，可以为患者的咨询、试验分层和干预时机提供有价值的见解。我们的研究旨在通过探究基因型-表型相关和可能影响疾病进展的因素，准确地确定SOD1-ALS的临床特征。本研究是对Emilia-Romagna、Piedmont和Valle d'Aosta三个意大利地区两个登记册中的SOD1-ALS队列进行的回顾性观察研究。在2204名进行基因型鉴定的ALS患者中，有2.5%携带了SOD1突变，男女比例为0.83。SOD1-ALS患者年龄较小，并且更频繁报告有ALS和/或FTD的家族史。与没有ALS相关基因突变的患者相比，SOD1-ALS的存活时间更长。然而，不同的SOD1突变在存活时间上存在相当大的变异性，L39V、G42S、G73S和D91N突变的平均存活时间不到一年。在SOD1-ALS中，多元分析显示，除年龄较大的发病年龄和高进展速度外，位于外显子2或高度保守基因位点的突变预示着较差的存活率。相反，在共病症中，癌症史与较长的存活时间独立相关。在整体疾病较慢的情况下，SOD1-ALS呈现出与潜在突变位点和特定临床预后因素相关的一定异质性，包括癌症史。揭示调节SOD1-ALS表型异质性的因素可能有助于提高即将到来的治疗方法的功效。© 2023. 作者，独家授权给Springer-Verlag GmbH Germany。

Uncovering distinct features and trajectories of amyotrophic lateral sclerosis (ALS) associated with SOD1 mutations (SOD1-ALS) can provide valuable insights for patient' counseling and stratification for trials, and interventions timing. Our study aims to pinpoint distinct clinical characteristics of SOD1-ALS by delving into genotype-phenotype correlations and factors that potentially impact disease progression.This is a retrospective observational study of a SOD1-ALS cohort from two Italian registers situated in the regions of Emilia-Romagna, Piedmont and Valle d'Aosta.Out of 2204 genotyped ALS patients, 2.5% carried SOD1 mutations, with a M:F ratio of 0.83. SOD1-ALS patients were younger, and more frequently reported a family history of ALS and/or FTD. SOD1-ALS had a longer survival compared to patients without ALS-associated gene mutations. However, here was considerable variability in survival across distinct SOD1 mutations, with an average survival of less than a year for the L39V, G42S, G73S, D91N mutations. Among SOD1-ALS, multivariate analysis showed that, alongside established clinical prognostic factors such as advanced age at onset and high progression rate at diagnosis, mutations located in exon 2 or within highly conserved gene positions predicted worse survival. Conversely, among comorbidities, cancer history was independently associated with longer survival.Within the context of an overall slower disease, SOD1-ALS exhibits some degree of heterogeneity linked to the considerable genetic diversity arising from the multitude of potential mutations sites and specific clinical prognostic factors, including cancer history. Revealing the factors that modulate the phenotypic heterogeneity of SOD1-ALS could prove advantageous in improving the efficacy of upcoming therapeutic approaches.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.