Predictors for progression in amyotrophic lateral sclerosis associated to SOD1 mutation: insight from two population-based registries

Martinelli, Ilaria; Ghezzi, Andrea; Zucchi, Elisabetta; Gianferrari, Giulia; Ferri, Laura; Moglia, Cristina; Manera, Umberto; Solero, Luca; Vasta, Rosario; Canosa, Antonio; Grassano, Maurizio; Brunetti, Maura; Mazzini, Letizia; De Marchi, Fabiola; Simonini, Cecilia; Fini, Nicola; Vinceti, Marco; Pinti, Marcello; Chiò, Adriano; Calvo, Andrea; Mandrioli, Jessica

doi:10.1007/s00415-023-11963-0

Cited by 4 publications

(1 citation statement)

References 47 publications

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“…When examining variations between different mutations, SOD1 mutations appear to be slightly more prevalent in females. SOD1 patients tend to be younger than other ALS patients [40] and have a longer survival compared to patients without ALS-associated gene mutations (except for the mutations p.L39V, p.G42S, p.G73S, and p.D91N [41]). The typical clinical presentation involves the lower limbs and, like TARDBP cases, evolves toward a classical form of ALS.…”

Section: Comparison With Other Monogenic Motor Neuron Diseasesmentioning

confidence: 97%

Variability in Clinical Phenotype in TARDBP Mutations: Amyotrophic Lateral Sclerosis Case Description and Literature Review

Lombardi,

Corrado,

Piola

et al. 2023

Genes

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Mutations in the 43 kDa transactive-response (TAR)-DNA-binding protein (TARDBP) are associated with 2–5% of familial Amyotrophic Lateral Sclerosis (ALS) cases. TAR DNA-Binding Protein 43 (TDP-43) is an RNA/DNA-binding protein involved in several cellular mechanisms (e.g., transcription, pre-mRNA processing, and splicing). Many ALS-linked TARDBP mutations have been described in the literature, but few phenotypic data on monogenic TARDBP-mutated ALS are available. In this paper, (1) we describe the clinical features of ALS patients carrying mutations in the TARDBP gene evaluated at the Tertiary ALS Center at Maggiore della Carità University Hospital, Novara, Italy, from 2010 to 2020 and (2) present the results of our review of the literature on this topic, analyzing data obtained for 267 patients and highlighting their main clinical and demographic features.

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Section: Comparison With Other Monogenic Motor Neuron Diseasesmentioning

confidence: 97%

Variability in Clinical Phenotype in TARDBP Mutations: Amyotrophic Lateral Sclerosis Case Description and Literature Review

Lombardi,

Corrado,

Piola

et al. 2023

Genes

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Changes in Cerebrospinal Fluid Concentrations of Selenium Species Induced by Tofersen Administration in Subjects with Amyotrophic Lateral Sclerosis Carrying SOD1 Gene Mutations

Vinceti,

Urbano,

Filippini

et al. 2024

Biol Trace Elem Res

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the brain and spinal cord motor neurons. On 25 April 2023, the drug tofersen, an antisense oligonucleotide, received the US Food and Drug Administration approval for treating ALS in adults carrying mutations of the SOD1 gene. We aimed at assessing whether cerebrospinal fluid concentrations of selenium, an element of both toxicological and nutritional interest possibly involved in disease etiology and progression, are modified by tofersen administration. We determined concentrations of selenium species by anion exchange chromatography hyphenated to inductively coupled plasma-dynamic reaction cell-mass spectrometry and overall selenium by using inductively coupled plasma sector-field mass spectrometry, at baseline and 6 months after active tofersen treatment in ten Italian ALS patients carrying the SOD1 gene mutation. Concentrations of total selenium and many selenium species substantially increased after the intervention, particularly of inorganic (tetravalent and hexavalent) selenium and of the organic species selenomethionine and a compound co-eluting with the selenocystine standard. Overall, these findings suggest that tofersen treatment markedly alters selenium status and probably the redox status within the central nervous system, possibly due to a direct effect on neurons and/or the blood–brain barrier. Further studies are required to investigate the biological and clinical relevance of these findings and how they might relate to the pharmacological effects of the drug and to disease progression.

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Tofersen for SOD1 ALS

Everett,

Bucelli

2024

Neurodegenerative Disease Management

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition affecting the motor system. The heterogenous nature of ALS complicates trial design. Genetic forms of ALS present an opportunity to intervene in a less heterogeneous population. ALS associated with gain of function mutations in SOD1 make ‘knock-down’ strategies an attractive therapeutic approach. Tofersen, an antisense oligonucleotide that reduces expression of SOD1 via RNAase mediated degradation of SOD1 mRNA, has shown robust effects on ALS biomarkers. While a Phase III trial of tofersen failed to meet its primary end point, open label extension data suggests that tofersen slows progression of SOD1 ALS.

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Predictors for progression in amyotrophic lateral sclerosis associated to SOD1 mutation: insight from two population-based registries

Cited by 4 publications

References 47 publications

Variability in Clinical Phenotype in TARDBP Mutations: Amyotrophic Lateral Sclerosis Case Description and Literature Review

Variability in Clinical Phenotype in TARDBP Mutations: Amyotrophic Lateral Sclerosis Case Description and Literature Review

Changes in Cerebrospinal Fluid Concentrations of Selenium Species Induced by Tofersen Administration in Subjects with Amyotrophic Lateral Sclerosis Carrying SOD1 Gene Mutations

Tofersen for SOD1 ALS

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