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April 2022; 8 (2) Research ArticleOpen Access

ALS in Finland

Major Genetic Variants and Clinical Characteristics of Patients With and Without the C9orf72 Hexanucleotide Repeat Expansion

View ORCID ProfileHannu Laaksovirta, View ORCID ProfileJyrki Launes, Lilja Jansson, View ORCID ProfileBryan J. Traynor, View ORCID ProfileKarri Kaivola, View ORCID ProfilePentti J. Tienari
First published March 14, 2022, DOI: https://doi.org/10.1212/NXG.0000000000000665
Hannu Laaksovirta
From the Department of Neurology (H.L., K.K., P.J.T.), Helsinki University Hospital; Translational Immunology (H.L., L.J., K.K., P.J.T.), Research Programs Unit, University of Helsinki; Department of Psychology and Logopedics (J.L.), University of Helsinki, Finland; and Neuromuscular Diseases Research Section (B.J.T.), Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD.
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  • ORCID record for Hannu Laaksovirta
Jyrki Launes
From the Department of Neurology (H.L., K.K., P.J.T.), Helsinki University Hospital; Translational Immunology (H.L., L.J., K.K., P.J.T.), Research Programs Unit, University of Helsinki; Department of Psychology and Logopedics (J.L.), University of Helsinki, Finland; and Neuromuscular Diseases Research Section (B.J.T.), Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD.
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  • For correspondence: jyrki.launes@gmail.com
Lilja Jansson
From the Department of Neurology (H.L., K.K., P.J.T.), Helsinki University Hospital; Translational Immunology (H.L., L.J., K.K., P.J.T.), Research Programs Unit, University of Helsinki; Department of Psychology and Logopedics (J.L.), University of Helsinki, Finland; and Neuromuscular Diseases Research Section (B.J.T.), Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD.
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  • For correspondence: lilja.jansson@hus.fi
Bryan J. Traynor
From the Department of Neurology (H.L., K.K., P.J.T.), Helsinki University Hospital; Translational Immunology (H.L., L.J., K.K., P.J.T.), Research Programs Unit, University of Helsinki; Department of Psychology and Logopedics (J.L.), University of Helsinki, Finland; and Neuromuscular Diseases Research Section (B.J.T.), Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD.
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  • For correspondence: traynorb@mail.nih.gov
Karri Kaivola
From the Department of Neurology (H.L., K.K., P.J.T.), Helsinki University Hospital; Translational Immunology (H.L., L.J., K.K., P.J.T.), Research Programs Unit, University of Helsinki; Department of Psychology and Logopedics (J.L.), University of Helsinki, Finland; and Neuromuscular Diseases Research Section (B.J.T.), Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD.
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  • For correspondence: karri.kaivola@helsinki.fi
Pentti J. Tienari
From the Department of Neurology (H.L., K.K., P.J.T.), Helsinki University Hospital; Translational Immunology (H.L., L.J., K.K., P.J.T.), Research Programs Unit, University of Helsinki; Department of Psychology and Logopedics (J.L.), University of Helsinki, Finland; and Neuromuscular Diseases Research Section (B.J.T.), Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD.
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  • For correspondence: pentti.tienari@hus.fi
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ALS in Finland
Major Genetic Variants and Clinical Characteristics of Patients With and Without the C9orf72 Hexanucleotide Repeat Expansion
Hannu Laaksovirta, Jyrki Launes, Lilja Jansson, Bryan J. Traynor, Karri Kaivola, Pentti J. Tienari
Neurol Genet Apr 2022, 8 (2) e665; DOI: 10.1212/NXG.0000000000000665

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Abstract

Background and Objectives To analyze the frequencies of major genetic variants and the clinical features in Finnish patients with amyotrophic lateral sclerosis (ALS) with or without the C9orf72 hexanucleotide repeat expansion.

Methods A cohort of patients with motor neuron disease was recruited between 1993 and 2020 at the Helsinki University Hospital and 2 second-degree outpatient clinics in Helsinki. Finnish ancestry patients with ALS fulfilled the diagnosis according to the revised El Escorial criteria and the Awaji-criteria. Two categories of familial ALS (FALS) were used. A patient was defined FALS-A if at least 1 first- or second-degree family member had ALS, and FALS-NP, if family members had additional neurologic or psychiatric endophenotypes.

Results Of the 815 patients, 25% had FALS-A and 45% FALS-NP. C9orf72 expansion (C9pos) was found in 256 (31%) of all patients, in 58% of FALS-A category, in 48% of FALS-NP category, and in 23 or 17% of sporadic cases using the FALS-A or FALS-NP definition. C9pos or SOD1 p.D91A homozygosity was found in 328 (40%) of the 815 patients. We compared demographic and clinical characteristics between C9pos and patients with unknown cause of ALS (Unk). We found that the age at onset was significantly earlier and survival markedly shorter in the C9pos vs Unk patients with ALS. The shortest survival was found in bulbar-onset male C9pos patients, whereas the longest survival was found in Unk limb-onset males. Older age at onset associated consistently with shorter survival in C9pos and Unk patients in both limb-onset and bulbar-onset groups. There were no significant differences in the frequencies of bulbar-onset and limb-onset patients in C9pos and Unk groups. 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.

Discussion These results provide further evidence for the short survival of C9orf72-associated ALS. A prominent role of the C9orf72 and SOD1 variants was found in the Finnish population. An unusually high frequency of C9pos was also found among patients with sporadic ALS. The enrichment of these 2 variants likely contributes to the high incidence of ALS in Finland.

Glossary

ALS=
amyotrophic lateral sclerosis;
AUC=
area under the curve;
FALS=
familial ALS;
FTD=
frontotemporal dementia;
GWAS=
genome-wide association study;
MST=
mean survival time;
OR=
odds ratio;
SALS=
sporadic ALS

Footnotes

  • Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.

  • The Article Processing Charge was funded by the funding body, University of Helsinki.

  • Received October 4, 2021.
  • Accepted in final form January 26, 2022.
  • Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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