背景:肌萎缩侧索硬化症(ALS)是一种致命的神经退行性疾病。近年来,新的ALS致病基因的不断发现增强了对ALS基因型-表型关系的认识,有助于疾病进展预测,为基因诊断提供更全面的依据。
方法:纳入2014年1月至2022年12月在北京协和医院神经内科就诊并符合修订后的ElEscorial诊断标准的1672例ALS患者。收集临床数据,对C9ORF72基因进行全外显子组测序和动态突变筛选,并对患者的临床表型和基因型进行分析。
结果:1672例ALS患者的平均发病年龄为52.6±11.2岁(范围为17-85岁),就诊时的中位疾病持续时间为14个月(四分位距9-24个月,范围2-204个月)。男女比例为833:839。患者包括297例(17.8%)球发病,198(11.8%)患有连ail臂/腿综合征,89(5.3%)患有家族性ALS,52(3.1%)伴有额颞叶痴呆(FTD)。在175例患者(占队列的10.5%)中检测到与ALS相关的致病变异,最常见的突变是SOD1,FUS,ANXA11在家族性ALS患者中,56.2%(50/89)有基因突变,相比之下,散发性ALS病例为7.9%(125/1583)。从表型-基因型相关性的角度来看,(1)在ALS-FTD患者中,最常见的基因突变是ANXA11和C9ORF72重复扩增.患有连ail臂/腿综合征的患者更频繁地携带SOD1,ANXA11和hnRNPA1的突变;(2)尽管遗传异质性,据观察,FUS和NEK1的突变在男性中更常见,FUS突变患者发病年龄较小;SOD1和SQSTM1突变更有可能出现在下肢发病中.
结论:本研究通过对1672例患者的大规模临床数据和基因分析,提供了中国ALS患者遗传特征的综合数据。发病年龄的差异,发病部位,不同基因型ALS患者的临床表型和临床表型可以帮助临床医生更好地预测疾病进展,为精准诊断和个体化治疗提供依据。
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. In recent years, continuous discoveries of new ALS-causing genes have enhanced the understanding of the genotype-phenotype relationship in ALS, aiding in disease progression prediction and providing a more comprehensive basis for genetic diagnosis.
METHODS: A total of 1672 ALS patients who visited the Neurology Department of Peking Union Medical College Hospital between January 2014 and December 2022 and met the revised El Escorial diagnostic criteria were included. Clinical data were collected, whole exome sequencing and dynamic mutation screening of the C9ORF72 gene were performed, and the clinical phenotypes and genotypes of the patients were analyzed.
RESULTS: The average age of onset for the 1672 ALS patients was 52.6 ± 11.2 years (range 17-85 years), with a median disease duration of 14 months at the time of visit (interquartile range 9-24 months, range 2-204 months). The male to female ratio was 833:839. The patients included 297 (17.8%) with bulbar onset, 198 (11.8%) with flail arm/leg syndrome, 89 (5.3%) with familial ALS, and 52 (3.1%) with concomitant frontotemporal dementia (FTD). Pathogenic variants associated with ALS were detected in 175 patients (10.5% of the cohort), with the most common mutations being SOD1, FUS, and ANXA11. Among patients with familial ALS, 56.2% (50/89) had genetic mutations, compared to 7.9% (125/1583) in sporadic ALS cases. From the perspective of phenotype-genotype correlation, (1) In ALS-FTD patients, the most common genetic mutations were ANXA11 and C9ORF72 repeat expansions. Patients with flail arm/leg syndrome more frequently carried mutations in SOD1, ANXA11, and hnRNPA1; (2) Despite genetic heterogeneity, it was observed that mutations in FUS and NEK1 were more common in males, and patients with FUS mutations had a younger age of onset; mutations in SOD1 and SQSTM1 were more likely to present with lower limb onset.
CONCLUSIONS: This study provides comprehensive data on the genetic characteristics of ALS patients in
China through large-scale clinical data and genetic analysis of 1672 cases. Differences in age of onset, onset site, and clinical phenotype among ALS patients with different genotypes can help clinicians better predict disease progression and provide a basis for precise diagnosis and individualized treatment.