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Benatar, M., Robertson, J. & Andersen, P. M. (2025). Amyotrophic lateral sclerosis caused by SOD1 variants: from genetic discovery to disease prevention. Lancet Neurology, 24(1), 77-86
Open this publication in new window or tab >>Amyotrophic lateral sclerosis caused by SOD1 variants: from genetic discovery to disease prevention
2025 (English)In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 24, no 1, p. 77-86Article, review/survey (Refereed) Published
Abstract [en]

Pathogenic variants in the superoxide dismutase 1 (SOD1) gene were the first identified genetic cause of amyotrophic lateral sclerosis (ALS), in 1993. This discovery enabled the development of transgenic rodent models for studying the biology of SOD1 ALS. The understanding that SOD1 ALS is driven by a toxic gain-of-function mutation has led to therapeutic strategies that aim to lower concentrations of SOD1 protein, an endeavour that has been complicated by the phenotypic heterogeneity of SOD1 ALS. The successful development of genetically targeted therapies to reduce SOD1 expression, together with a better understanding of pre-symptomatic disease and the discovery of neurofilament light protein as a susceptibility/risk biomarker that predicts phenoconversion, has ushered in a new era of trials that aim to prevent clinically manifest SOD1 ALS. The 30-year journey from gene discovery to gene therapy has not only uncovered the pathophysiology of SOD1 ALS, but has also facilitated the development of biomarkers that should aid therapy development for all forms of ALS.

Place, publisher, year, edition, pages
Elsevier, 2025
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-233539 (URN)10.1016/S1474-4422(24)00479-4 (DOI)39706636 (PubMedID)2-s2.0-85212347495 (Scopus ID)
Funder
Swedish Research Council, 2017-03100Knut and Alice Wallenberg Foundation, 2012.0091Knut and Alice Wallenberg Foundation, 2023.0460Knut and Alice Wallenberg Foundation, 2020.0232Knut and Alice Wallenberg Foundation, 2014.0305,Ulla-Carin Lindquist Foundation for ALS-ResearchThe Swedish Brain Foundation
Available from: 2025-01-10 Created: 2025-01-10 Last updated: 2025-01-10Bibliographically approved
Malmström, N., Öhlén, J., Jakobsson Larsson, B., Nilsson, S., Nygren, I., Andersen, P. M. & Ozanne, A. (2024). Adolescents' challenging and grief-filled transitions when living with a parent with ALS: a qualitative interpretive study. Social Science and Medicine, 354, Article ID 117063.
Open this publication in new window or tab >>Adolescents' challenging and grief-filled transitions when living with a parent with ALS: a qualitative interpretive study
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2024 (English)In: Social Science and Medicine, ISSN 0277-9536, E-ISSN 1873-5347, Vol. 354, article id 117063Article in journal (Refereed) Published
Abstract [en]

Objective: The study aimed to explore the meaning for adolescents of living with a parent with amyotrophic lateral sclerosis (ALS).

Methods: The design is qualitative. Interviews were conducted between December 2020 and April 2022 with 11 adolescents (8-25 y), living in households with a parent with ALS in Sweden. The analysis was phenomenologically hermeneutical.

Results: The adolescents were in a difficult and exposed situation, especially if the parent had a severe disability and assistant care providers were in the home. Witnessing the gradual loss of the parent in an indefinite battle against time, while still needing them, elicited grief-filled and hard-to-manage emotions. Everyday life was turned upside down, resulting in greater responsibility for the adolescents, not only in helping with household chores and assisting the ill parent, but also in emotionally protecting both parents. It forced the adolescents to mature faster and put their own life on hold, triggering experiences of being limited. This, together with changing family roles yet being more attached to home, reinforced the imbalance in the adolescents' lives. The interpreted whole of the adolescents' narratives revealed that living with a parent with ALS meant a challenging and grieving transition during an already transition-filled adolescence, which left the adolescents struggling to keep a foothold on a life torn apart.

Conclusion: The unbalanced life situation may hinder the adolescents' identity formation and emancipation, which are developmentally important for managing a healthy and independent adulthood. The results emphasize the importance of early targeted support to reach this vulnerable group in order to secure their health.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Adolescent, Amyotrophic lateral sclerosis, Child, Family support, Motor neuron disease, Phenomenological hermeneutics
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-227779 (URN)10.1016/j.socscimed.2024.117063 (DOI)2-s2.0-85197197123 (Scopus ID)
Funder
University of Gothenburg
Available from: 2024-07-08 Created: 2024-07-08 Last updated: 2024-07-08Bibliographically approved
Winroth, I., Börjesson, A., Andersen, P. M. & Karlsson, T. (2024). Cognitive deficits in ALS patients with SOD1 mutations. Journal of Clinical and Experimental Neuropsychology, 46(7), 669-682
Open this publication in new window or tab >>Cognitive deficits in ALS patients with SOD1 mutations
2024 (English)In: Journal of Clinical and Experimental Neuropsychology, ISSN 1380-3395, E-ISSN 1744-411X, Vol. 46, no 7, p. 669-682Article in journal (Refereed) Published
Abstract [en]

Objective: Cognitive decline is common in patients with amyotrophic lateral sclerosis (ALS), especially in carriers of the mutation C9ORF72HRE. However, cognitive impairment is poorly understood in carriers of mutations in other genes causing ALS. We performed a comprehensive neuropsychological testing in patients with mutations in the SOD1 (mSOD1) gene.

Methods: We examined 5 cognitive domains in 48 symptomatic patients with either hereditary or sporadic ALS. These were compared with 37 matched controls.

Results: Carriers of SOD1-mutations and sporadic ALS had circumscribed deficits, but in a pattern different from C9ORF72HRE. All groups had deficits in working memory, although mSOD1-carriers significantly outperform sporadic ALS and C9ORF72HRE in an attention-driven visuospatial task involving copying a complex figure. Carriers of the D90A-SOD1 mutation overall performed as well as or better than carriers of other SOD1-mutations, except complex working memory. Bayesian analyses suggest (with evidence of moderate strength) that tasks involving the language domain did not differ between controls, mSOD1 and sporadic ALS.

Conclusion: Distinct cognitive impairments are prevalent in different ALS-syndromes and vary in patients with different pathogenic SOD1 mutations. The type and degree of impairment differed depending on genotype and was significantly least pronounced in patients homozygous for the D90A SOD1 mutation. The presence of cognitive deficits may influence optimal clinical management and intervention. We propose that cognitive assessment should be included in the routine examination of new patients suspected of ALS. Neuropsychological assessment is an under-recognized outcome parameter in clinical drug trials.

Place, publisher, year, edition, pages
Routledge, 2024
Keywords
Amyotrophic lateral sclerosis, C9ORF72, cognition, fronto-temporal dementia, SOD1, working memory
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-229620 (URN)10.1080/13803395.2024.2393366 (DOI)001310397200001 ()39258714 (PubMedID)2-s2.0-85203546334 (Scopus ID)
Funder
Region Västerbotten, RV-967096Umeå University, 223-2989Swedish Association of Persons with Neurological DisabilitiesUlla-Carin Lindquist Foundation for ALS-Research, 648946The Swedish Brain Foundation, FO2020- 0353
Available from: 2024-09-17 Created: 2024-09-17 Last updated: 2024-10-24Bibliographically approved
Van Damme, P., Al-Chalabi, A., Andersen, P. M., Chiò, A., Couratier, P., De Carvalho, M., . . . Weber, M. (2024). European academy of neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European reference network for neuromuscular diseases (ERN EURO-NMD). European Journal of Neurology, 31(6), Article ID e16264.
Open this publication in new window or tab >>European academy of neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European reference network for neuromuscular diseases (ERN EURO-NMD)
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2024 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 31, no 6, article id e16264Article in journal (Refereed) Published
Abstract [en]

Background: This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS).

Methods: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available.

Results: A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence [NICE] guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease-modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end-of-life management.

Conclusions: This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available.

Place, publisher, year, edition, pages
John Wiley & Sons, 2024
Keywords
disease-modifying treatment, gastrostomy, guideline, multidisciplinary care, non-invasive ventilation
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-223082 (URN)10.1111/ene.16264 (DOI)001182520500001 ()38470068 (PubMedID)2-s2.0-85187465125 (Scopus ID)
Available from: 2024-04-15 Created: 2024-04-15 Last updated: 2024-06-19Bibliographically approved
Rosén, C., Mitre, B., Nellgård, B., Axelsson, M., Constantinescu, R., Munch Andersen, P., . . . Rosén, H. (2024). High levels of neurofilament light and YKL-40 in cerebrospinal fluid are related to poor outcome in ALS. Journal of the Neurological Sciences, 463, Article ID 123112.
Open this publication in new window or tab >>High levels of neurofilament light and YKL-40 in cerebrospinal fluid are related to poor outcome in ALS
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2024 (English)In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 463, article id 123112Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a neurological disease without effective treatment. No pathognomonic test can diagnose ALS in sporadic cases. Routine investigation in suspected cases includes neurological examination, imaging of the brain and spine and electromyography supported by blood and cerebrospinal fluid (CSF) analyses. The ALS diagnosis is made by clinical judgement and results from examinations. We aimed to study if the CSF biomarkers neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), YKL-40, soluble amyloid precursor protein (sAPP) α and β, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were associated with ALS diagnosis and could predict disease progression. Eighty-one patients with suspected ALS were included after referral to the neurological clinic at Sahlgrenska University Hospital. Fifty-nine patients were diagnosed having ALS, while 22 patients were given alternative diagnoses and labeled ALS mimics. Finally, 25 age-matched neurologically intact individuals were used as controls.

ALS patients had significantly higher CSF levels of NFL than controls and mimics. Levels of YKL-40 and GFAP were significantly higher in ALS patients compared with controls. No difference was found between study groups when comparing levels of sAPPα, sAPPβ and sTREM2. Further, elevated levels of NFL and YKL-40 were associated with an increased hazard of death and the annual decline in ALSFRS-R. We also found that patients with elevated levels of both NFL and YKL-40 had a particularly poor prognosis. The results demonstrate the usefulness of CSF biomarkers in the diagnosis and prognostication of ALS.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Amyotrophic lateral sclerosis, Brain damage markers, Diagnosis, GFAP, Neurofilament light protein, Prognosis, YKL-40
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:umu:diva-227877 (URN)10.1016/j.jns.2024.123112 (DOI)2-s2.0-85197603960 (Scopus ID)
Funder
EU, Horizon Europe, 101053962Familjen Erling-Perssons Stiftelse, FO2022-0270Stiftelsen Gamla TjänarinnorThe Swedish Brain FoundationEU, Horizon 2020, 860197Ulla-Carin Lindquist Foundation for ALS-ResearchSwedish Research Council, 2017-00915Swedish Research Council, 2022-00732Alzheimerfonden, AF-930351Alzheimerfonden, AF-939721Alzheimerfonden, AF-968270The Swedish Brain Foundation, FO2017–0243The Swedish Brain Foundation, ALZ2022–0006
Available from: 2024-07-15 Created: 2024-07-15 Last updated: 2024-07-15Bibliographically approved
Marriott, H., Spargo, T. P., Al Khleifat, A., Andersen, P. M., Başak, N. A., Cooper-Knock, J., . . . Iacoangeli, A. (2024). Mutations in the tail and rod domains of the neurofilament heavy-chain gene increase the risk of ALS. Annals of Clinical and Translational Neurology, 11(7), 1775-1786
Open this publication in new window or tab >>Mutations in the tail and rod domains of the neurofilament heavy-chain gene increase the risk of ALS
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2024 (English)In: Annals of Clinical and Translational Neurology, E-ISSN 2328-9503, Vol. 11, no 7, p. 1775-1786Article in journal (Refereed) Published
Abstract [en]

Objective: Neurofilament heavy-chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk.

Methods: Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta-analyses of published case–control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole-genome sequencing data.

Results: Fixed-effects meta-analysis found that rare (MAF <1%) missense variants in the tail domain of NEFH increase ALS risk (OR 4.55, 95% CI 2.13–9.71, p < 0.0001). In Project MinE, ultrarare NEFH variants increased ALS risk (OR 1.37 95% CI 1.14–1.63, p = 0.0007), with rod domain variants (mostly intronic) appearing to drive the association (OR 1.45 95% CI 1.18–1.77, pMadsen–Browning = 0.0007, pSKAT-O = 0.003). While in the tail domain, ultrarare (MAF <0.1%) pathogenic missense variants were also associated with higher risk of ALS (OR 1.94, 95% CI 0.86–4.37, pMadsen–Browning = 0.039), supporting the meta-analysis results. Finally, several tail in-frame deletions were also found to affect disease risk, however, both protective and pathogenic deletions were found in this domain, highlighting an intricated architecture that requires further investigation.

Interpretation: We showed that NEFH tail missense and in-frame deletion variants, and intronic rod variants are risk factors for ALS. However, they are not variants of large effect, and their functional impact needs to be clarified in further studies. Therefore, their inclusion in routine genetic screening panels should be reconsidered.

Place, publisher, year, edition, pages
John Wiley & Sons, 2024
National Category
Medical Genetics and Genomics
Identifiers
urn:nbn:se:umu:diva-226966 (URN)10.1002/acn3.52083 (DOI)001228829600001 ()38775181 (PubMedID)2-s2.0-85195660655 (Scopus ID)
Available from: 2024-06-24 Created: 2024-06-24 Last updated: 2025-02-10Bibliographically approved
Forsberg, K., Karlsborg, M., Salvesen, L., Svenstrup, K., Winroth, I., Berntsson, H. & Andersen, P. M. (2024). Precisionsmedicinsk genterapi har bromsat utveckling av ALS: [SOD1 gene therapy delays ALS disease progression]. Läkartidningen, 121, Article ID 24044.
Open this publication in new window or tab >>Precisionsmedicinsk genterapi har bromsat utveckling av ALS: [SOD1 gene therapy delays ALS disease progression]
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2024 (English)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 121, article id 24044Article in journal (Refereed) Published
Abstract [en]

We present a patient with familial amyotrophic lateral sclerosis caused by an aggressive A4S mutation in the SOD1 gene. In 2020, the patient was enrolled in the VALOR SOD1 gene therapy phase-3 trial. At screening, the ALSFRS-R score was 41 (48 is normal) and the level of CSF-neurofilament L (an indicator of ongoing neuronal damage) was 11 000 ng/L (ref <650 ng/L). In the four years following enrollment, the patient received monthly intrathecal treatment with tofersen, an antisense oligonucleotide compound that inhibits SOD1 protein expression and hence lowers the synthesis of toxic SOD1 protein species. Side effects have been minimal and mostly attributed to the spinal taps. The patient remains ambulatory with an active social lifestyle. The ALSFRS-R score has in the past 18 months stabilized around 35-37, CSF-NfL is 1 290 ng/L and plasma-NfL is 12 (reference <13). This is the first documented arresting intervention in a patient with ALS in Sweden.

Place, publisher, year, edition, pages
Läkartidningen Förlag AB, 2024
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-224167 (URN)38666665 (PubMedID)2-s2.0-85191426677 (Scopus ID)
Available from: 2024-05-16 Created: 2024-05-16 Last updated: 2024-05-17Bibliographically approved
Benatar, M., Hansen, T., Rom, D., Geist, M. A., Blaettler, T., Camu, W., . . . Levine, T. (2024). Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Neurology, 23(7), 687-699
Open this publication in new window or tab >>Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial
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2024 (English)In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 23, no 7, p. 687-699Article in journal (Refereed) Published
Abstract [en]

Background: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.

Methods: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.

Findings: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI –0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).

Interpretation: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.

Funding: Orphazyme.

Place, publisher, year, edition, pages
Elsevier, 2024
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-226731 (URN)10.1016/S1474-4422(24)00134-0 (DOI)2-s2.0-85195405864 (Scopus ID)
Available from: 2024-06-24 Created: 2024-06-24 Last updated: 2024-06-24Bibliographically approved
Roos, A.-K., Stenvall, E., Kockum, E. S., Åman Grönlund, K., Alstermark, H., Wuolikainen, A., . . . Forsberg, K. (2024). Small striatal huntingtin inclusions in patients with motor neuron disease with reduced penetrance and intermediate HTT gene expansions. Human Molecular Genetics, 33(22), 1966-1974
Open this publication in new window or tab >>Small striatal huntingtin inclusions in patients with motor neuron disease with reduced penetrance and intermediate HTT gene expansions
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2024 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 33, no 22, p. 1966-1974Article in journal (Refereed) Published
Abstract [en]

Short tandem repeat expansions in the human genome are overrepresented in a variety of neurological disorders. It was recently shown that huntingtin (HTT) repeat expansions with full penetrance, i.e. 40 or more CAG repeats, which normally cause Huntington's disease (HD), are overrepresented in patients with amyotrophic lateral sclerosis (ALS). Whether patients carrying HTT repeat expansions with reduced penetrance, (36-39 CAG repeats), or alleles with intermediate penetrance, (27-35 CAG repeats), have an increased risk of ALS has not yet been investigated. Here, we examined the role of HTT repeat expansions in a motor neuron disease (MND) cohort, searched for expanded HTT alleles, and investigated correlations with phenotype and neuropathology. MND patients harboring C9ORF72 hexanucleotide repeat expansions (HREs) were included, to investigate whether HTT repeat expansions were more common in this group. We found a high prevalence of intermediate (range 5.63%-6.61%) and reduced penetrance (range 0.57%-0.66%) HTT gene expansions in this cohort compared to other populations of European ancestry, but no differences between the MND cohort and the control cohort were observed, regardless of C9ORF72HRE status. Upon autopsy of three patients with intermediate or reduced penetrance HTT alleles, huntingtin inclusions were observed in the caudate nucleus and frontal lobe, but no significant somatic mosaicism was detected in different parts of the nervous system. Thus, we demonstrate, for the first time, huntingtin inclusions in individuals with MND and intermediate and reduced penetrance HTT repeat expansions but more clinicopathological investigations are needed to further understand the impact of HTT gene expansion-related pleiotropy.

Place, publisher, year, edition, pages
Oxford University Press, 2024
Keywords
C9ORF72HRE, Amyotrophic lateral sclerosis, huntingtin inclusions, somatic mosaicism
National Category
Neurosciences Medical Genetics and Genomics
Identifiers
urn:nbn:se:umu:diva-232510 (URN)10.1093/hmg/ddae137 (DOI)001311874700001 ()39270726 (PubMedID)2-s2.0-85208854699 (Scopus ID)
Funder
The Swedish Brain Foundation, FO 2022–0309The Swedish Brain Foundation, FO2023–0088Swedish Research Council, 2012–3167Swedish Research Council, 2017–03100Region Jämtland Härjedalen, JLL-980693Knut and Alice Wallenberg Foundation, 2012.0091Knut and Alice Wallenberg Foundation, 2014.0305Knut and Alice Wallenberg Foundation, 2020.0232Swedish Association of Persons with Neurological DisabilitiesUlla-Carin Lindquist Foundation for ALS-Research, 2023.16Västerbotten County Council, RV-993493Västerbotten County Council, RV-996140Västerbotten County Council, RV-939329Västerbotten County Council, RV56103–7002829Västerbotten County Council, RV-941598Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
Available from: 2024-12-02 Created: 2024-12-02 Last updated: 2025-02-10Bibliographically approved
Leykam, L., Forsberg, K., Nordström, U., Hjertkvist, K., Öberg, A., Jonsson, E., . . . Zetterström, P. (2024). Specific analysis of SOD1 enzymatic activity in CSF from ALS patients with and without SOD1 mutations. Neurobiology of Disease, 202, Article ID 106718.
Open this publication in new window or tab >>Specific analysis of SOD1 enzymatic activity in CSF from ALS patients with and without SOD1 mutations
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2024 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 202, article id 106718Article in journal (Refereed) Published
Abstract [en]

Mutations in superoxide dismutase-1 (SOD1) are a cause of hereditary amyotrophic lateral sclerosis (ALS) through a gain-of-function mechanism involving unfolded mutant SOD1. Intrathecal gene therapy using the antisense-oligo-nucleotide drug tofersen to reduce SOD1 expression delays disease progression and has recently been approved in the United States and the European Union. However, the discovery of children homozygous for inactivating SOD1 mutations developing the SOD1 Deficiency Syndrome (ISODDES) with injury to the motor system suggests that a too low SOD1 antioxidant activity may be deleterious in humans. Measuring SOD1 activity in cerebrospinal fluid (CSF) in tofersen-treated patients is recommended but difficult due to low concentration and the presence of the isoenzyme SOD3. We here present a sensitive method to assess SOD1 activity by removing SOD3 from CSF samples using highly specific immobilized antibodies and subsequent measurement of the SOD activity. We validated the method on 171 CSF samples from ALS patients with and without mutations and controls and used paired erythrocyte samples for comparison. We found that in ALS patients with wildtype SOD1, the SOD1 activity in CSF was equal to controls, but patients with mutant SOD1 show lower activity in CSF, even for patients with mutants previously reported to have full activity in erythrocytes. Activity variation in CSF was large among patients carrying the same SOD1 mutation and larger than in erythrocytes and in post-mortem nervous tissue. Additionally, we identified a discrepancy between the SOD1 activity and protein level measured with ELISA in both CSF and erythrocytes. Since antibodies used for SOD1 ELISA-quantification are raised against the natively folded wildtype SOD1, the concentration of mutant SOD1s may be underestimated. Analysis of SOD1 enzymatic activity in CSF is therefore a more reliable way to monitor the effect of SOD1-lowering drugs.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
ALS, Amyotrophic lateral sclerosis, Cerebrospinal fluid, SOD1 activity, SOD1 loss-of-function
National Category
Neurosciences Other Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-231645 (URN)10.1016/j.nbd.2024.106718 (DOI)001349855900001 ()39490682 (PubMedID)2-s2.0-85207756868 (Scopus ID)
Available from: 2024-11-19 Created: 2024-11-19 Last updated: 2024-11-19Bibliographically approved
Projects
Genetic factors causing sporadic and familial amyotrophic lateral sclerosis (ALS/MND) with or without dementia [2009-03548_VR]; Umeå UniversityGenetic factors causing sporadic and familial amyotrophic lateral sclerosis (ALS/MND) with or without frontotemporal dementia. [2012-03167_VR]; Umeå UniversityAnsökan VD ALS EU (JPND HC-559-024) [2013-07590_VR]; Umeå UniversityJPND Pilot Studies on Preventive Strategies 2013. ONWebDUALS, ONTology-based Web Database for Understanding Amyotrophic Lateral Sclerosis [2014-07505_VR]; Umeå UniversityOn the Origin of ALS: Clinical-genetic research into the etiology of ALS with or without dementia: Translation into Inhibition of SOD1 prion as a novel new intervention for treating ALS [2017-03100_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-0094-5429

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