肌萎缩侧索硬化的基因诊断及进展

Progress in gene diagnosis of amyotrophic lateral sclerosis

肌萎缩侧索硬化(ALS)作为一种复杂的神经退行性疾病,其早期精准诊断十分困难。随着ALS相关遗传学的研究进展,越来越多的ALS致病及风险基因被发现,尤其是针对相关致病基因的基因治疗临床试验的开展,促进了基因诊断应用于ALS临床实践的必要性。本文介绍了目前常用的基因检测方法的优缺点,常见ALS致病基因的突变频率、基因型和表型的关系以及基因检测的策略。我国ALS患者最常见的致病基因是超氧化物歧化酶1(SOD1)基因,而在高加索人群中最常见的致病基因是C9ORF72基因。针对家族性ALS患者应建议其进行ALS致病基因panel的筛查,如果检测结果为阴性,需要行全外显子或者全基因组检测以寻找新的致病基因;对于散发性ALS患者,SOD1基因和C9ORF72基因均应作为常规筛查;此外,如果患者具有特殊的临床表型,病情进展迅速、病程极慢、合并认知损害、锥体外系症状等,为了进一步明确诊断和判断预后亦应进行相应的基因检测。

Amyotrophic lateral sclerosis(ALS)is a complex neurodegenerative disease,for which early diagnosis is still very difficult up to now.With more and more ALS pathogenic and risk genes discovered,and especially the application of clinical trials of gene therapy in ALS,the genetic diagnosis becomes far more essential in ALS clinical practice.This presentation is a general introduction to the advantages and disadvantages of the commonly used gene detection methods,the key features of the pathogenic genes,the relationship between genotype and phenotype and the strategy of risk gene detection.The most common causative gene in Chinese ALS patients is superoxide dismutase(SOD1)gene,while in the Caucasian population is chromosome 9 open reading frame 72(C9ORF72)gene.Familial ALS should be recommended for screening of ALS pathogenic gene panels.If negative,whole exome or genome sequencing is recommended to locate new pathogenic genes.The SOD1 and C9ORF72 should be routinely screened no matter in familial or sporadic form of ALS.In addition,if the patient has a special clinical phenotype,such as rapid or slow progression,cognitive impairment or extrapyramidal symptoms,genetic detection will be of great value for the diagnosis.