| 1. |
- van Rheenen, Wouter, et al.
(author)
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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
- 2016
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1043-1048
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Journal article (peer-reviewed)abstract
- To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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| 2. |
- Al-Chalabi, Ammar, et al.
(author)
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July 2017 ENCALS statement on edaravone
- 2017
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In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : TAYLOR & FRANCIS LTD. - 2167-8421 .- 2167-9223. ; 18:7-8, s. 471-474
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Journal article (peer-reviewed)abstract
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| 3. |
- Andersen, Peter M., 1962-, et al.
(author)
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Caregivers’ divergent perspectives on patients’ well-being and attitudes towards hastened death in Germany, Poland and Sweden
- 2022
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In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis. - 2167-8421 .- 2167-9223. ; 23:3-4, s. 252-262
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Journal article (peer-reviewed)abstract
- Background: During the course of amyotrophic lateral sclerosis (ALS), patients and their families are faced with existential decisions concerning life-prolonging and -shortening measures. Correct anticipation of patient’s well-being and preferences is a prerequisite for patient-centered surrogate decision making.Methods: In Germany (N = 84), Poland (N = 77) and Sweden (N = 73) patient-caregiver dyads were interviewed. Standardized questionnaires on well-being (ADI-12 for depressiveness; ACSA for global quality of life) and wish for hastened death (SAHD) were used in ALS patients. Additionally, caregivers were asked to fill out the same questionnaires by anticipating patients’ perspective (surrogate perspective).Results: Caregivers significantly underestimated patients’ well-being in Germany and Poland. For Swedish caregivers, there were just as many who underestimated and overestimated well-being. The same was true for wish for hastened death in all three countries. For Swedish and Polish patients, caregivers’ estimation of well-being was not even associated with patients’ responses and the same was true for estimation of wish for hastened death in all three countries. Older caregivers and those with the most frequent encounter with the patient were the closest in their rating of well-being and wish for hastened death to the patients’ actual state, while caregivers with chronic disease him/herself were more likely to underestimate patient’s well-being.Discussion: Despite distinct cultural differences, there was a clear discrepancy between patients’ and caregivers’ perspective on patients’ well-being and preferences towards life in all three countries. This possible bias in caregivers’ judgment needs to be taken into account in surrogate decision making.
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| 4. |
- Andersen, Peter M., et al.
(author)
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EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS) : revised report of an EFNS task force
- 2012
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In: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 19:3, s. 360-E24
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Journal article (peer-reviewed)abstract
- Background: The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak. Objectives: To provide evidence-based or expert recommendations for the diagnosis and management of ALS based on a literature search and the consensus of an expert panel. Methods: All available medical reference systems were searched, and original papers, meta-analyses, review papers, book chapters and guidelines recommendations were reviewed. The final literature search was performed in February 2011. Recommendations were reached by consensus. Recommendations: Patients with symptoms suggestive of ALS should be assessed as soon as possible by an experienced neurologist. Early diagnosis should be pursued, and investigations, including neurophysiology, performed with a high priority. The patient should be informed of the diagnosis by a consultant with a good knowledge of the patient and the disease. Following diagnosis, the patient and relatives/carers should receive regular support from a multidisciplinary care team. Medication with riluzole should be initiated as early as possible. Control of symptoms such as sialorrhoea, thick mucus, emotional lability, cramps, spasticity and pain should be attempted. Percutaneous endoscopic gastrostomy feeding improves nutrition and quality of life, and gastrostomy tubes should be placed before respiratory insufficiency develops. Non-invasive positive-pressure ventilation also improves survival and quality of life. Maintaining the patient's ability to communicate is essential. During the entire course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end-of-life care should be discussed early with the patient and carers, respecting the patient's social and cultural background.
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| 5. |
- Andersen, Peter M., 1962-, et al.
(author)
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Therapeutic decisions in ALS patients : cross-cultural differences and clinical implications
- 2018
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In: Journal of Neurology. - : Springer Berlin/Heidelberg. - 0340-5354 .- 1432-1459. ; 265:7, s. 1600-1606
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Journal article (peer-reviewed)abstract
- Objective: Quantitative analysis of decision-making on therapeutic options in different sociocultural context in amyotrophic lateral sclerosis (ALS).Methods: ALS patients (n = 244) were consecutively recruited in Germany (n = 83), Poland (n = 83), and Sweden (n = 78) in a prospective cross-cultural study (www.NEEDSinALS.com). They were interviewed on preferences for therapeutic techniques including invasive (IV) and non-invasive ventilation (NIV), as well as percutaneous endoscopic gastrostomy (PEG) and on hypothetical termination of these using quantitative questions. Using standardized questionnaires, religiousness, personal values, quality of life, and depressiveness were assessed.Results: NIV was most frequently used in Germany and PEG in Sweden. Swedish patients were most liberal on initiation and termination of PEG, NIV and IV. Polish patients were mostly undecided and were least likely to consider discontinuing supportive management. Current use was partly associated with age, gender and state of physical function; also, financial support explained some variance. Future preferences on therapeutic options from the patient’s perspective were also closely associated with cultural factors. The more oriented towards traditional and conservative values, the less likely patients were to decide for invasive therapeutic devices (IV, PEG), the least likely to have ideations to discontinue any device and the more likely to have an undecided attitude.Conclusions: Current use of therapeutic options is determined by medical condition in analogy to clinical guidelines. For future considerations, other factors such as cultural background are crucial, yielding hurdles to be regarded in the implementation of advanced directives in a multicultural environment.
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| 6. |
- Baird, Zachariah Steven, et al.
(author)
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Vapor-Liquid Equilibrium of Ionic Liquid 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-enium Acetate and Its Mixtures with Water
- 2020
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In: Journal of Chemical and Engineering Data. - : American Chemical Society (ACS). - 0021-9568 .- 1520-5134. ; 65:5, s. 2405-2421
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Journal article (peer-reviewed)abstract
- Ionic liquids have the potential to be used forextracting valuable chemicals from raw materials. These processesoften involve water, and after extraction, the water or otherchemicals must be removed from the ionic liquid, so it can bereused. To help in designing such processes, we present data onthe vapor−liquid equilibrium of the system containing protic ionicliquid 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-enium acetate,water, acetic acid, and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene. Earlier studies have only focused on mixtures of water and anionic liquid with a stoichiometric ratio of the ions. Here, we alsoinvestigated mixtures containing an excess of the acid or basecomponent because in real systems with protic ionic liquids, theamount of acid and base in the mixture can vary. We modeled thedata using both the ePC-SAFT and NRTL models, and we compared the performance of different modeling strategies. We alsoexperimentally determined the vapor composition for a few of the samples, but none of the modeling strategies tested couldaccurately predict the concentration of the acid and base components in the vapor phase.
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| 7. |
- Benatar, Michael, et al.
(author)
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Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01) : a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial
- 2024
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In: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 23:7, s. 687-699
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Journal article (peer-reviewed)abstract
- 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.
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| 8. |
- Brenner, David, et al.
(author)
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Hot-spot KIF5A mutations cause familial ALS
- 2018
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In: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 141, s. 688-697
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Journal article (peer-reviewed)abstract
- Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 x 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p. Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 x 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.
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| 9. |
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| 10. |
- Cudkowicz, Merit, et al.
(author)
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Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study) : a randomised, double-blind, placebo-controlled phase 3 trial
- 2021
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In: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 20:10, s. 821-831
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Journal article (peer-reviewed)abstract
- BACKGROUND: There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function.METHODS: The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60-90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178) has also been completed, but will be reported separately.FINDINGS: Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5-51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4-48·1) weeks. Change from baseline in supine SVC at 12 weeks was -6·73% with levosimendan and -6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI -2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI -15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis.INTERPRETATION: Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation.FUNDING: Orion Corporation.
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