Clinical characterization of common pathogenic variants of SOD1-ALS in Germany.

Autor: Wiesenfarth M; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany. maximilian.wiesenfarth@rku.de., Forouhideh-Wiesenfarth Y; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany., Elmas Z; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany., Parlak Ö; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany., Weiland U; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany., Herrmann C; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany., Schuster J; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany.; German Centre for Neurodegenerative Diseases (DZNE) Site Ulm, 89081, Ulm, Germany., Freischmidt A; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany., Müller K; Institute of Human Genetics, Ulm University and Ulm University Medical Center, 89081, Ulm, Germany., Siebert R; Institute of Human Genetics, Ulm University and Ulm University Medical Center, 89081, Ulm, Germany., Günther K; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany., Fröhlich E; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany., Knehr A; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany., Simak T; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany., Bachhuber F; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany., Regensburger M; Department of Molecular Neurology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany.; Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, 91054, Erlangen, Germany., Petri S; Department of Neurology, Hannover Medical School, 30625, Hannover, Germany., Klopstock T; Department of Neurology with Friedrich-Baur-Institute, LMU University Hospital, LMU Munich, 80336, Munich, Germany.; German Centre for Neurodegenerative Diseases (DZNE) Site Munich, 81377, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), 81377, Munich, Germany., Reilich P; Department of Neurology with Friedrich-Baur-Institute, LMU University Hospital, LMU Munich, 80336, Munich, Germany., Schöberl F; Department of Neurology with Friedrich-Baur-Institute, LMU University Hospital, LMU Munich, 80336, Munich, Germany., Schumann P; Ambulanzpartner Soziotechnologie GmbH, 13353, Berlin, Germany., Körtvélyessy P; Department of Neurology, Center for ALS and other Motor Neuron Disorders, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 13353, Berlin, Germany.; German Centre for Neurodegenerative Diseases (DZNE) Site Magdeburg, 39120, Magdeburg, Germany., Meyer T; Department of Neurology, Center for ALS and other Motor Neuron Disorders, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 13353, Berlin, Germany., Ruf WP; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany., Witzel S; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany., Tumani H; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany.; German Centre for Neurodegenerative Diseases (DZNE) Site Ulm, 89081, Ulm, Germany., Brenner D; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany.; German Centre for Neurodegenerative Diseases (DZNE) Site Ulm, 89081, Ulm, Germany., Dorst J; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany.; German Centre for Neurodegenerative Diseases (DZNE) Site Ulm, 89081, Ulm, Germany., Ludolph AC; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany.; German Centre for Neurodegenerative Diseases (DZNE) Site Ulm, 89081, Ulm, Germany.
Jazyk: angličtina
Zdroj: Journal of neurology [J Neurol] 2024 Oct; Vol. 271 (10), pp. 6667-6679. Date of Electronic Publication: 2024 Aug 14.
DOI: 10.1007/s00415-024-12564-1
Abstrakt: Pathogenic variants in the Cu/Zn superoxide dismutase (SOD1) gene can be detected in approximately 2% of sporadic and 11% of familial amyotrophic lateral sclerosis (ALS) patients in Europe. We analyzed the clinical phenotypes of 83 SOD1-ALS patients focusing on patients carrying the most frequent (likely) pathogenic variants (R116G, D91A, L145F) in Germany. Moreover, we describe the effect of tofersen treatment on ten patients carrying these variants. R116G patients showed the most aggressive course of disease with a median survival of 22.0 months compared to 198.0 months in D91A and 87.0 months in L145F patients (HR 7.71, 95% CI 2.89-20.58 vs. D91A; p < 0.001 and HR 4.25, 95% CI 1.55-11.67 vs. L145F; p = 0.02). Moreover, R116G patients had the fastest median ALSFRS-R progression rate with 0.12 (IQR 0.07-0.20) points lost per month. Median diagnostic delay was 10.0 months (IQR 5.5-11.5) and therefore shorter compared to 57.5 months (IQR 14.0-83.0) in D91A (p < 0.001) and 21.5 months (IQR 5.8-38.8) in L145F (p = 0.21) carriers. As opposed to D91A carriers (50.0%), 96.2% of R116G (p < 0.001) and 100.0% of L145F (p = 0.04) patients reported a positive family history. During tofersen treatment, all patients showed a reduction of neurofilament light chain (NfL) serum levels, independent of the SOD1 variant. Patients with SOD1-ALS carrying R116G, D91A, or L145F variants show commonalities, but also differences in their clinical phenotype, including a faster progression rate with shorter survival in R116G, and a comparatively benign disease course in D91A carriers.
(© 2024. The Author(s).)
Databáze: MEDLINE
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