Olsen Cathrine Goberg, Busk Øyvind Løvold, Aanjesen Tori Navestad, Alstadhaug Karl Bjørnar, Bjørnå Ingrid Kristine, Braathen Geir Julius, Breivik Kristin Lif, Demic Natasha, Flemmen Heidi Øyen, Hallerstig Erika, HogenEsch Ineke, Holla Øystein Lunde, Jøntvedt Anne Berit, Kampman Margitta T, Kleveland Grethe, Kvernmo Helene Ballo, Ljøstad Unn, Maniaol Angelina, Morsund Åse Hagen, Nakken Ola, Novy Camilla, Rekand Tiina, Schlüter Katrin, Schüler Stephan, Tveten Kristian, Tysnes Ole-Bjørn, Holmøy Trygve, Høyer Helle
Department of Medical Genetics, Telemark Hospital Trust, Skien, Norway.
Institute of Clinical Medicine, University of Oslo, Nordbyhagen, Norway.
Neuroepidemiology. 2022;56(4):271-282. doi: 10.1159/000525091. Epub 2022 May 16.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons. In Europe, disease-causing genetic variants have been identified in 40-70% of familial ALS patients and approximately 5% of sporadic ALS patients. In Norway, the contribution of genetic variants to ALS has not yet been studied. In light of the potential development of personalized medicine, knowledge of the genetic causes of ALS in a population is becoming increasingly important. The present study provides clinical and genetic data on familial and sporadic ALS patients in a Norwegian population-based cohort.
Blood samples and clinical information from ALS patients were obtained at all 17 neurological departments throughout Norway during a 2-year period. Genetic analysis of the samples involved expansion analysis of C9orf72 and exome sequencing targeting 30 known ALS-linked genes. The variants were classified using genotype-phenotype correlations and bioinformatics tools.
A total of 279 ALS patients were included in the study. Of these, 11.5% had one or several family members affected by ALS, whereas 88.5% had no known family history of ALS. A genetic cause of ALS was identified in 31 individuals (11.1%), among which 18 (58.1%) were familial and 13 (41.9%) were sporadic. The most common genetic cause was the C9orf72 expansion (6.8%), which was identified in 8 familial and 11 sporadic ALS patients. Pathogenic or likely pathogenic variants of SOD1 and TBK1 were identified in 10 familial and 2 sporadic cases. C9orf72 expansions dominated in patients from the Northern and Central regions, whereas SOD1 variants dominated in patients from the South-Eastern region.
In the present study, we identified several pathogenic gene variants in both familial and sporadic ALS patients. Restricting genetic analysis to only familial cases would miss more than 40 percent of those with a disease-causing genetic variant, indicating the need for genetic analysis in sporadic cases as well.
肌萎缩侧索硬化症（ALS）是一种影响运动神经元的神经退行性疾病。在欧洲，40%-70%的家族性ALS患者以及约5%的散发性ALS患者中已鉴定出致病基因变异。在挪威，基因变异对ALS的影响尚未得到研究。鉴于个性化医疗的潜在发展，了解人群中ALS的遗传病因变得越来越重要。本研究提供了挪威一个基于人群队列中的家族性和散发性ALS患者的临床和遗传数据。
在为期两年的时间里，从挪威所有17个神经科收集了ALS患者的血液样本和临床信息。样本的基因分析包括C9orf72的扩增分析以及针对30个已知ALS相关基因的外显子测序。使用基因型-表型相关性和生物信息学工具对变异进行分类。
本研究共纳入279例ALS患者。其中，11.5%有一名或多名家庭成员受ALS影响，而88.5%没有已知的ALS家族病史。在31名个体（11.1%）中确定了ALS的遗传病因，其中18例（58.1%）为家族性，13例（41.9%）为散发性。最常见的遗传病因是C9orf72扩增（6.8%），在8例家族性和11例散发性ALS患者中被鉴定出来。在10例家族性和2例散发性病例中鉴定出SOD1和TBK1的致病性或可能致病性变异。C9orf72扩增在北部和中部地区的患者中占主导，而SOD1变异在东南部地区的患者中占主导。
在本研究中，我们在家族性和散发性ALS患者中均鉴定出了几种致病基因变异。仅对家族性病例进行基因分析会遗漏超过40%携带致病基因变异的患者，这表明散发性病例也需要进行基因分析。
