Genetic Epidemiology of Amyotrophic Lateral Sclerosis in Norway: A 2-Year Population-Based Study

Olsen, Cathrine Goberg; Busk, Øyvind L.; Aanjesen, Tori Navestad; Alstadhaug, Karl Bjørnar; Bjørnå, Ingrid Kristine; Braathen, Geir J.; Breivik, Kyrre; Demic, Natasha; Flemmen, Heidi Øyen; Hallerstig, Erika; HogenEsch, Ineke; Holla, Øystein L.; 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, K.; Schüler, Stephan; Tveten, Kristian; Tysnes, Ole‐Bjørn; Holmøy, Trygve; Høyer, Helle

doi:10.1159/000525091

Cited by 10 publications

(4 citation statements)

References 48 publications

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“…Forty‐two related papers [6, 7, 22–61] were summarized and it was found that 178 of 9814 patients with ALS/FTD carried TBK1 variants, including 95 patients carrying LoF variants and 83 patients carrying missense variants (Table S4). Therefore, a meta‐analysis was performed of the frequency of TBK1 variants reported in ALS/FTD patients (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

TBK1 variants in Chinese patients with amyotrophic lateral sclerosis: Genetic analysis and clinical features

Zhao

Jiang

Lin

et al. 2023

Euro J of Neurology

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Background and purposeHaploinsufficiency of TANK‐binding kinase 1 (TBK1) loss‐of‐function (LoF) variants has been shown to be pathogenic in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the genetic spectrum of TBK1 and clinical features of ALS patients with TBK1 variants remain largely unknown in Asians.MethodsGenetic analysis was performed on 2011 Chinese ALS patients. Software was used to predict the deleteriousness of missense variants in TBK1. In addition, PubMed, Embase and Web of Science were searched for related literature.ResultsTwenty‐six TBK1 variants were identified in 33 of 2011 ALS patients, including six novel LoF variants (0.3%) and 20 rare missense variants, 12 of which were predicted to be deleterious (0.6%). In addition to TBK1 variants, 11 patients had other ALS‐related gene variants. Forty‐two previous studies found that the frequency of TBK1 variants was 1.81% in ALS/FTD patients. The frequency of TBK1 LoF variants in ALS was 0.5% (Asians 0.4%; Caucasian 0.6%) and that of missense variants was 0.8% (Asians 1.0%; Caucasian 0.8%). ALS patients with TBK1 LoF variants affecting the kinase domain had a significantly younger age of onset than patients carrying LoF variants affecting the coiled coil domains CCD1 and CCD2. FTD has a frequency of 10% in Caucasian ALS patients with TBK1 LoF variants, which was not found in our cohort.ConclusionOur study expanded the genotypic spectrum of ALS patients with TBK1 variants and found that the clinical manifestations of TBK1 carriers are diverse.

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Section: Resultsmentioning

confidence: 99%

TBK1 variants in Chinese patients with amyotrophic lateral sclerosis: Genetic analysis and clinical features

Zhao

Jiang

Lin

et al. 2023

Euro J of Neurology

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“…First, there is significant variability in the occurrence of mutations in key ALS-related genes among different ethnic groups [ 28 ]. Specifically for the Nordic countries, there is a higher occurrence of hexanucleotide expansion mutations in the C9orf72 gene, and a geographical gradient (more prevalent in the northern regions) has been observed in Finnish and Norwegian populations [ 29 , 30 ]. However, the specific distribution of these mutations within Sweden remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Increased incidence of motor neuron disease in Sweden: a population-based study during 2002–2021

Imrell,

Fang,

Ingre

et al. 2024

J Neurol

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Background Motor neuron diseases (MND), with amyotrophic lateral sclerosis constituting most cases, are rare conditions of unknown etiology. There have been reports of an increase in incidence during the latter half of the twentieth century in various Western countries, including Sweden. This study provides updated data on the incidence of MND in Sweden during the last 20 years. Methods Data was obtained from the Swedish National Patient Register on individuals diagnosed with MND from 2002 to 2021 and analysed in relation to group level data for the entire Swedish population. Incidence rates were calculated and presented in relation to year, age, sex, and region. Results In the early 2000s, there was a crude incidence rate of 3.5–3.7 per 100,000 person-years, which then increased to 4.0–4.6 from 2008 onward. Age standardization to the starting year (2002) partially mitigated this increase. The incidence rate was greater among men compared to women and was highest within the age range of 70 to 84 years. There were indications of a higher incidence rate in the northernmost parts of the country, although the difference was not statistically significant. Conclusions The incidence rate of MND in Sweden now seems to have surpassed 4 cases per 100,000 person-years. This is higher when compared to both other European countries and previous Swedish studies. It remains to be determined if this increase reflects an actual increasing incidence of MND in Sweden or is due to other factors such as better registry coverage.

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“…11,49 C9orf72 is the most common ALS risk gene in Norway and accounted for 6.8% of all ALS cases in a recent study. 50 We did not have genotypic information and were not able to assess possible gene-environment interactions.…”

Section: Discussionmentioning

confidence: 99%

Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis

Vaage,

Meyer,

Landgraff

et al. 2024

Neurology

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Background and ObjectivesObservational studies have demonstrated an increased amyotrophic lateral sclerosis (ALS) risk among professional athletes in various sports. For moderately increased levels of physical activity and fitness, the results are diverging. Through a cohort study, we aimed to assess the relationship between indicators of physical activity and fitness (self-reported physical activity and resting heart rate) and long-term ALS risk. MethodsFrom a large Norwegian cardiovascular health survey (1985)(1986)(1987)(1988)(1989)(1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999), we collected information on self-reported physical activity in leisure time, resting heart rate, and other cardiovascular risk factors. Patients with ALS were identified through health registries covering the whole population. We fitted Cox proportional hazard models to assess the risk of ALS according to levels of self-reported physical activity in 3 categories (1: sedentary; 2: minimum 4 hours per week of walking or cycling; 3: minimum 4 hours per week of recreational sports or hard training), and resting heart rate modeled both on the continuous scale and as quartiles of distribution. ResultsOut of 373,696 study participants (mean 40.9 [SD 1.1] years at inclusion), 504 (41.2% women) developed ALS during a mean follow-up time of 27.2 (SD 5.0) years. Compared with participants with the lowest level of physical activity, the hazard ratio was 0.71 (95% CI 0.53-0.95) for those with the highest level. There were no clear associations between resting heart rate and ALS in the total sample. In men, the hazard ratio of ALS was 0.71 (95% CI 0.53-0.95) for those reporting moderate levels of physical activity and 0.59 (95% CI 0.42-0.84) for those reporting high levels, compared with those reporting low levels. Men with resting heart rate in the lowest quartile had 32% reduced risk of ALS (hazard ratio 0.68, 95% CI 0.49-0.94) compared with those in the second highest quartile. In women, no association was detected between neither self-reported levels of physical activity nor resting heart rate and ALS risk. DiscussionIndicators of high levels of physical activity and fitness are associated with a reduced risk of ALS more than 30 years later in men, but not in women.

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Genetic Epidemiology of Amyotrophic Lateral Sclerosis in Norway: A 2-Year Population-Based Study

Cited by 10 publications

References 48 publications

TBK1 variants in Chinese patients with amyotrophic lateral sclerosis: Genetic analysis and clinical features

TBK1 variants in Chinese patients with amyotrophic lateral sclerosis: Genetic analysis and clinical features

Increased incidence of motor neuron disease in Sweden: a population-based study during 2002–2021

Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis

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