148 7例肌萎缩侧索硬化患者地域分布特点 的临床研究

研究背景：肌萎缩侧索硬化(Amyotrophic lateral sclerosiS，ALS)是累及上、下运动神经元的退行性疾病，好发于中老年，患者多数在出现症状后的3-5年内死于呼吸肌受累引起的呼吸衰竭。既往研究提示ALS在发病率、临床特征及致病突变分布等方面存在地域差异。北京协和医院是国内较大的ALS诊治中心之一，患者居住地来源广泛，但仍以北方为主。本研究拟通过对北京协和医院ALS队列的分析，以及与既往研究发表的数据对比，探索我国ALS患者的地域分布特点。
研究方法：纳入2013年3月至2020年1月期间在北京协和医院就诊的、符合2015年修订版E1 Escorial诊断标准ALS患者，并除外未成年起病及缺乏长期居住地数据的患者。按居住地将患者分为南方、北方两组，首先比较南、北方患者在起病年龄、性别比、起病部位等临床特征及ALS相关突变分布的差异。预后方面，定义结局事件为死亡或气管切开，首先采用单因素COX回归分析居住地南方／：11：方等因素对结局事件的影响，之后将p<O．1的变量纳入多因素COX模型，寻找影响预后的独立危险因素。此外，通过比较7个自然地理区患者的临床特点，实现对ALS地域分布更精细的研究。
研究结果：本研究共纳入1487名ALS患者，其中北方患者1096名(73．7％)，南方患者391名(26．3％)。北方患者的起病年龄显著大于南方患者(54．1±lO．7岁VS5l+2±11．3岁，p<O．001)，且服用利鲁唑的比例更低(53％VS 63％，p=O．005)。两组患者在性别比、起病部位、临床表现类型、起病到确诊时间等方面无显著差异，无创呼吸机使用率和经皮胃造瘘比率也近似。共有52名北方患者和24名南方患者筛查出了ALS相关基因的突变。SODl突变在两组患者中都是最常见的。单因素COX回归中，北方患者出现结局事件的时间显著早于南方患者(HR=I．306，95％CI 1．030-1．656，p=O．027)。多因素COX回归显示，起病年龄大、球部起病、起病到确诊时间≤1年、入组时ALSFRS—R评分较低、未经无创呼吸机或经皮胃造瘘治疗均是预后较差的独立危险因素，而居住地变量不显著。7个自然地理区相比，西南和西北地区患者起病年龄显著小于东北及华北患者，华北地区患者球部起病比例显著小于华中和西南地区患者，各区域患者生存曲线无显著差异。
研究结论：北京协和医院ALS队列以北方患者为主，与南方患者相比，北方患者起病年龄较大，服用利鲁唑比例较低。居住地南／北方并非影响预后的独立因素。南北方患者ALS相关突变的组成相近，两组患者中最常见的致病基因均为SODl。不同自然地理区ALS患者在起病年龄、起病部位等方面有显著差异。

Research Background: Amyotrophic Lateral Sclerosis (ALS) is a degenerative disease affecting both upper and lower motor neurons, predominantly occurring in middle-aged and elderly individuals. Most patients die of respiratory failure caused by involvement of respiratory muscles within 3 to 5 years after symptom onset. Previous studies have indicated that ALS exhibits regional disparities in terms of incidence, clinical characteristics, and distribution of pathogenic mutations. Peking Union Medical College Hospital (PUMCH) is one of the largest ALS diagnosis and treatment centers in China, with a broad range of patient residential origins but a predominantly northern cohort. This study aims to explore the geographic distribution characteristics of ALS patients in China through analysis of the PUMCH ALS cohort and comparison with previously published research data.

Research Methods: We enrolled ALS patients who attended PUMCH between March 2013 and January 2020 and met the 2015 revised El Escorial diagnostic criteria for ALS, excluding those with onset before adulthood and those lacking long-term residence data. Patients were divided into southern and northern groups based on their residence. First, we compared differences in clinical characteristics including age at onset, sex ratio, onset site, and the distribution of ALS-related mutations between southern and northern patients. For prognosis assessment, we defined the outcome endpoint as death or tracheotomy. We first conducted univariate COX regression analysis to evaluate the impact of factors such as southern/northern residence on the outcome endpoint, then included variables with p<0.1 in the multivariate COX model to identify independent risk factors for prognosis. Additionally, we performed a more refined investigation of ALS geographic distribution by comparing clinical characteristics of patients from 7 natural geographic regions.

Research Results: A total of 1487 ALS patients were enrolled in this study, including 1096 northern patients (73.7%) and 391 southern patients (26.3%). Northern patients had a significantly older age at onset (54.1±10.7 years vs 51.2±11.3 years, p<0.001) and a lower proportion of receiving riluzole treatment (53% vs 63%, p=0.005). No significant differences were observed between the two groups in sex ratio, onset site, clinical phenotype, time from onset to diagnosis, rate of non-invasive ventilation (NIV) use, or percutaneous endoscopic gastrostomy (PEG) placement rate. Pathogenic mutations in ALS-related genes were identified in 52 northern patients and 24 southern patients, with SOD1 mutations being the most common in both groups. Univariate COX regression analysis showed that northern patients experienced the outcome endpoint significantly earlier than southern patients (HR=1.306, 95%CI 1.030-1.656, p=0.027). Multivariate COX regression analysis revealed that older age at onset, bulbar onset, time from onset to diagnosis ≤1 year, lower ALSFRS-R score at enrollment, and absence of NIV or PEG treatment were all independent risk factors for poor prognosis, while residential region was not a significant prognostic factor. When comparing the 7 natural geographic regions, patients from southwest and northwest China had a significantly younger age at onset than those from northeast and north China, and the proportion of bulbar-onset patients in north China was significantly lower than that in central and southwest China. No significant differences were found in survival curves among the different regions.

Research Conclusions: The PUMCH ALS cohort was dominated by northern patients. Compared with southern patients, northern patients had an older age at onset and a lower rate of riluzole usage. Residential region (southern vs northern) was not an independent prognostic factor. The composition of ALS-related mutations was similar between the two groups, with SOD1 being the most common pathogenic gene in both cohorts. Patients from different natural geographic regions exhibited significant differences in age at onset, onset site, and other clinical characteristics.