{"title":"在中国,各种基因突变的肌萎缩侧索硬化症患者表现出不同的运动表型和存活率。","authors":"Qirui Jiang, Junyu Lin, Qianqian Wei, Tianmi Yang, Yanbing Hou, Lingyu Zhang, Ruwei Ou, Yi Xiao, Shichan Wang, Xiaoting Zheng, Chunyu Li, Huifang Shang","doi":"10.1136/jmg-2024-109909","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by progressive degeneration of motor neurons. Genetic factors have a substantial impact on ALS. Therefore, this study aimed to explore the correlation between genotype (<i>SOD1, TARDBP, FUS, C9orf72</i>) and phenotype in ALS.</p><p><strong>Methods: </strong>Genetic analysis was performed on 2038 patients with ALS, among which 1696 patients with sporadic ALS (SALS) as controls for genotype-phenotype analysis, and 1602 SALS as controls for survival analysis. Logistic regression and Cox proportional hazards models were used for statistical analysis.</p><p><strong>Results: </strong>A total of 172 patients with ALS with the gene mutations were included in the statistical analysis (<i>SOD1</i>, n=65; <i>FUS</i>, n=43; <i>TARDBP</i>, n=27; <i>C9orf72</i>, n=37). <i>SOD1</i> mutations were more frequent in flail leg phenotype (OR 7.317, p=0.001) and less in bulbar phenotype (OR 0.222, p=0.038). <i>C9orf72</i> expansions exhibited higher frequency in bulbar phenotype (OR 2.770, p=0.008). <i>SOD1</i> and <i>FUS</i> mutations were significantly associated with earlier age of onset (HR 2.039, p<0.001; HR 1.762, p=0.001). The patients with <i>SOD1</i> mutations, <i>C9orf72</i> expansions and those carrying pathogenic <i>FUS</i> mutations had significantly increased death risk (HR 2.217, p<0.001; HR 1.694, p=0.008; HR 1.652, p=0.036). The increased risk of death in ALS with <i>C9orf72</i> expansions was significant in females (HR 2.419, p=0.014) but not in males (HR 1.442, p=0.128).</p><p><strong>Conclusion: </strong>Our study revealed distinct motor phenotypic tendencies in patients with ALS with different genotypes, indicating variations in the vulnerability of motor neurons during the disease's progression. Furthermore, we made novel discoveries regarding survival of different gene mutations, warranting further investigation.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"839-846"},"PeriodicalIF":3.5000,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Amyotrophic lateral sclerosis patients with various gene mutations show diverse motor phenotypes and survival in China.\",\"authors\":\"Qirui Jiang, Junyu Lin, Qianqian Wei, Tianmi Yang, Yanbing Hou, Lingyu Zhang, Ruwei Ou, Yi Xiao, Shichan Wang, Xiaoting Zheng, Chunyu Li, Huifang Shang\",\"doi\":\"10.1136/jmg-2024-109909\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by progressive degeneration of motor neurons. Genetic factors have a substantial impact on ALS. Therefore, this study aimed to explore the correlation between genotype (<i>SOD1, TARDBP, FUS, C9orf72</i>) and phenotype in ALS.</p><p><strong>Methods: </strong>Genetic analysis was performed on 2038 patients with ALS, among which 1696 patients with sporadic ALS (SALS) as controls for genotype-phenotype analysis, and 1602 SALS as controls for survival analysis. Logistic regression and Cox proportional hazards models were used for statistical analysis.</p><p><strong>Results: </strong>A total of 172 patients with ALS with the gene mutations were included in the statistical analysis (<i>SOD1</i>, n=65; <i>FUS</i>, n=43; <i>TARDBP</i>, n=27; <i>C9orf72</i>, n=37). <i>SOD1</i> mutations were more frequent in flail leg phenotype (OR 7.317, p=0.001) and less in bulbar phenotype (OR 0.222, p=0.038). <i>C9orf72</i> expansions exhibited higher frequency in bulbar phenotype (OR 2.770, p=0.008). <i>SOD1</i> and <i>FUS</i> mutations were significantly associated with earlier age of onset (HR 2.039, p<0.001; HR 1.762, p=0.001). The patients with <i>SOD1</i> mutations, <i>C9orf72</i> expansions and those carrying pathogenic <i>FUS</i> mutations had significantly increased death risk (HR 2.217, p<0.001; HR 1.694, p=0.008; HR 1.652, p=0.036). The increased risk of death in ALS with <i>C9orf72</i> expansions was significant in females (HR 2.419, p=0.014) but not in males (HR 1.442, p=0.128).</p><p><strong>Conclusion: </strong>Our study revealed distinct motor phenotypic tendencies in patients with ALS with different genotypes, indicating variations in the vulnerability of motor neurons during the disease's progression. Furthermore, we made novel discoveries regarding survival of different gene mutations, warranting further investigation.</p>\",\"PeriodicalId\":16237,\"journal\":{\"name\":\"Journal of Medical Genetics\",\"volume\":\" \",\"pages\":\"839-846\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2024-08-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medical Genetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1136/jmg-2024-109909\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/jmg-2024-109909","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
摘要
背景:肌萎缩性脊髓侧索硬化症(ALS)是一种以运动神经元进行性变性为特征的破坏性神经退行性疾病。遗传因素对 ALS 有重大影响。因此,本研究旨在探讨 ALS 基因型(SOD1、TARDBP、FUS、C9orf72)与表型之间的相关性:对2038名ALS患者进行了基因分析,其中1696名散发性ALS(SALS)患者作为基因型-表型分析的对照,1602名SALS患者作为生存分析的对照。统计分析采用逻辑回归和考克斯比例危险模型:共有172名基因突变的ALS患者纳入统计分析(SOD1,n=65;FUS,n=43;TARDBP,n=27;C9orf72,n=37)。SOD1突变在小腿外翻表型中更为常见(OR 7.317,P=0.001),而在球部表型中则较少(OR 0.222,P=0.038)。C9orf72扩增在球部表型中出现的频率较高(OR 2.770,P=0.008)。SOD1和FUS突变与较早的发病年龄显著相关(HR 2.039,pSOD1突变、C9orf72扩增和携带致病性FUS突变者的死亡风险显著增加(HR 2.217,pC9orf72扩增在女性中显著(HR 2.419,p=0.014),但在男性中不显著(HR 1.442,p=0.128)):我们的研究揭示了不同基因型 ALS 患者的不同运动表型倾向,这表明在疾病进展过程中运动神经元的脆弱性存在差异。此外,我们还对不同基因突变的存活率有了新的发现,值得进一步研究。
Amyotrophic lateral sclerosis patients with various gene mutations show diverse motor phenotypes and survival in China.
Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by progressive degeneration of motor neurons. Genetic factors have a substantial impact on ALS. Therefore, this study aimed to explore the correlation between genotype (SOD1, TARDBP, FUS, C9orf72) and phenotype in ALS.
Methods: Genetic analysis was performed on 2038 patients with ALS, among which 1696 patients with sporadic ALS (SALS) as controls for genotype-phenotype analysis, and 1602 SALS as controls for survival analysis. Logistic regression and Cox proportional hazards models were used for statistical analysis.
Results: A total of 172 patients with ALS with the gene mutations were included in the statistical analysis (SOD1, n=65; FUS, n=43; TARDBP, n=27; C9orf72, n=37). SOD1 mutations were more frequent in flail leg phenotype (OR 7.317, p=0.001) and less in bulbar phenotype (OR 0.222, p=0.038). C9orf72 expansions exhibited higher frequency in bulbar phenotype (OR 2.770, p=0.008). SOD1 and FUS mutations were significantly associated with earlier age of onset (HR 2.039, p<0.001; HR 1.762, p=0.001). The patients with SOD1 mutations, C9orf72 expansions and those carrying pathogenic FUS mutations had significantly increased death risk (HR 2.217, p<0.001; HR 1.694, p=0.008; HR 1.652, p=0.036). The increased risk of death in ALS with C9orf72 expansions was significant in females (HR 2.419, p=0.014) but not in males (HR 1.442, p=0.128).
Conclusion: Our study revealed distinct motor phenotypic tendencies in patients with ALS with different genotypes, indicating variations in the vulnerability of motor neurons during the disease's progression. Furthermore, we made novel discoveries regarding survival of different gene mutations, warranting further investigation.
期刊介绍:
Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.