Submitted by: Niranjan Singh, MD
Edited by: Rebeca A. O'Bryan, MD
Laaksovirta H, Launes J, Jansson L, Traynor BJ, Kaivola K, Tienari PJ. ALS in Finland: Major Genetic Variants and Clinical Characteristics of Patients With and Without the C9orf72 Hexanucleotide Repeat Expansion. Neurol Genet. 2022;8(2):e665.
Summary: In this cohort study, the authors analyzed the frequency of major genetic variants and clinical features of patient with amyotrophic lateral sclerosis (ALS) with or without C9orf72 repeat expansion. The study included a cohort of patients with motor neuron disease between 1993 and 2020 at Helsinki University Hospital. Helsinki has one of the highest prevalence of motor neuron disease. Finnish ancestry patients fulfilled the diagnosis of ALS according to the revised El Escorial criteria and the Awaji-criteria. Two categories of familial ALS (FALS) were used. A patient was defined as FALS-A if at least 1 first- or second-degree family member had ALS, and definded as FALS-NP, if family members had additional neurologic or psychiatric endophenotypes. C9orf72 expansion (C9pos) was found in 256 (31%) of all patients. C9pos or SOD1 p.D91A homozygosity was found in 328 (40%) of the 815 patients. Age at onset was significantly lower and survival markedly decreased in the C9pos vs Unk patients with ALS. ALS-frontotemporal dementia (FTD) was more common in C9pos(17%) than in Unk (4%) patients, and of all patients with ALS-FTD, 70% were C9pos. SOD 1 was 9%.
Comments: The most common genetic cause of ALS in European populations is the hexanucleotide repeat expansion in the C9orf72 gene. In these populations, up to 50% of patients with FALS and about 5% of patients with sporadic ALS (SALS) carry this expansion (C9pos). The variant is much less common among Asian populations. FTD is another common phenotype associated with the C9orf72 expansion; it accounts for about 25% of familial FTD in Europeans and up to 86% of familial patients having both FTD and ALS. Finland is among the countries with the highest incidence of ALS in the world and has a very high prevalence of pathogenic gene. The frequency of the C9orf72 repeat expansion was 31% in the whole cohort, 48%–58% among FALS families, and 17%–23% in SALS depending on the FALS criteria used. Survival was shortest in bulbar C9pos and longest in limb-onset Unk patients. This does not reflected true population rate. An explanation for the high frequency of the C9orf72 and SOD1 variants as well as the high incidence of ALS in Finland could be the Finnish population structure, which is featured with genetic isolation and genetic bottlenecks resulting in geographically clustered founder populations. C9pos frequencies differ in patients with FALS and SALS from non Finnish countries and suggests that the Finnish population is an outlier in the frequency of the C9pos SALS.
Article of Similar Interest: Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, Chiò A, et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: A cross-sectional study. Lancet Neurol. 2012 Apr;11(4):323-30