| 41. |
- Andersen, Peter M., et al.
(författare)
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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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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 19:3, s. 360-E24
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Tidskriftsartikel (refereegranskat)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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| 42. |
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| 43. |
- Bergemalm, Daniel, et al.
(författare)
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Superoxide dismutase-1 and other proteins in inclusions from transgenic amyotrophic lateral sclerosis model mice
- 2010
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 114:2, s. 408-418
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Tidskriftsartikel (refereegranskat)abstract
- Mutant superoxide dismutase-1 (SOD1) causes amyotrophic lateral sclerosis (ALS) through a cytotoxic mechanism of unknown nature. A hallmark in ALS patients and transgenic mouse models carrying human SOD1 (hSOD1) mutations are hSOD1-immunoreactive inclusions in spinal cord ventral horns. The hSOD1 inclusions may block essential cellular functions or cause toxicity through sequestering of other proteins. Inclusions from four different transgenic mouse models were examined after density gradient ultracentrifugation. The inclusions are complex structures with heterogeneous densities and are disrupted by detergents. The aggregated hSOD1 was mainly composed of subunits that lacked the native stabilizing intra-subunit disulfide bond. A proportion of subunits formed hSOD1 oligomers or was bound to other proteins through disulfide bonds. Dense inclusions could be isolated and the protein composition was analyzed using proteomic techniques. Mutant hSOD1 accounted for half of the protein. Ten other proteins were identified. Two were cytoplasmic chaperones, four were cytoskeletal proteins, and 4 were proteins that normally reside in the endoplasmic reticulum (ER). The presence of ER proteins in inclusions containing the primarily cytosolic hSOD1 further supports the notion that ER stress is involved in ALS.
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| 44. |
- Birve, Anna, et al.
(författare)
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A novel SOD1 splice site mutation associated with familial ALS revealed by SOD activity analysis
- 2010
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:21, s. 4201-4206
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Tidskriftsartikel (refereegranskat)abstract
- More than 145 mutations have been found in the gene CuZn-Superoxide dismutase (SOD1) in patients with amyotrophic lateral sclerosis (ALS). The vast majority are easily detected nucleotide mutations in the coding region. In a patient from a Swiss ALS family with half-normal erythrocyte SOD1 activity, exon flanking sequence analysis revealed a novel thymine to guanine mutation 7 bp upstream of exon 4 (c.240-7T>G). The results of splicing algorithm analyses were ambiguous, but five out of seven analysis tools suggested a potential novel splice site that would add six new base pairs to the mRNA. If translated, this mRNA would insert Ser and Ile between Glu78 and Arg79 in the SOD1 protein. In fibroblasts from the patient, the predicted mutant transcript and the mutant protein were both highly expressed, and despite the location of the insertion into the metal ion-binding loop IV, the SOD1 activity appeared high. In erythrocytes, which lack protein synthesis and are old compared with cultured fibroblasts, both SOD1 protein and enzymic activity was 50% of controls. Thus, the usage of the novel splice site is near 100%, and the mutant SOD1 shows the reduced stability typical of ALS-associated mutant SOD1s. The findings suggests that this novel intronic mutation is causing the disease and highlights the importance of wide exon-flanking sequencing and transcript analysis combined with erythrocyte SOD1 activity analysis in comprehensive search for SOD1 mutations in ALS. We find that there are potentially more SOD1 mutations than previously reported.
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| 45. |
- Blasco, Helene, et al.
(författare)
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A Rare Motor Neuron Deleterious Missense Mutation in the DPYSL3 (CRMP4) Gene is Associated with ALS
- 2013
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Ingår i: Human Mutation. - : Wiley-Blackwell. - 1059-7794 .- 1098-1004. ; 34:7, s. 953-960
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Tidskriftsartikel (refereegranskat)abstract
- The dihydropyrimidinase-like 3 (DPYSL3) or Collapsin Response Mediator Protein 4a (CRMP4a) expression is modified in neurodegeneration and is involved in several ALS-associated pathways including axonal transport, glutamate excitotoxicity, and oxidative stress. The objective of the study was to analyze CRMP4 as a risk factor for ALS. We analyzed the DPYSL3/CRMP4 gene in French ALS patients (n=468) and matched-controls (n=394). We subsequently examined a variant in a Swedish population (184 SALS, 186 controls), and evaluated its functional effects on axonal growth and survival in motor neuron cell culture. The rs147541241:A>G missense mutation occurred in higher frequency among French ALS patients (odds ratio=2.99) but the association was not confirmed in the Swedish population. In vitro expression of mutated DPYSL3 in motor neurons reduced axonal growth and accelerated cell death compared with wild type protein. Thus, the association between the rs147541241 variant and ALS was limited to the French population, highlighting the geographic particularities of genetic influences (risks, contributors). The identified variant appears to shorten motor neuron survival through a detrimental effect on axonal growth and CRMP4 could act as a key unifier in transduction pathways leading to neurodegeneration through effects on early axon development.
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| 46. |
- Blumen, Sergiu C, et al.
(författare)
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Aggressive familial ALS with unusual brain MRI and a SOD1 gene mutation.
- 2010
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Ingår i: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders. - : Informa Healthcare. - 1466-0822 .- 1743-4483. ; 11:1-2, s. 228-231
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Tidskriftsartikel (refereegranskat)abstract
- We studied two sisters with rapidly progressing ALS starting at the ages of 46 and 48 years and leading to death after 14 months. Both fulfilled the El Escorial criteria for definite ALS and had marked upper motor neuron (UMN) predominance. Brain MRI, on fluid attenuation recovery (FLAIR) mode, showed outstanding hyperintensities of the precentral gyrus, centrum semiovale, corona radiata and along the corticospinal pathways in the brainstem. Screening for the SOD1 gene disclosed, at codon 140, a base substitution of adenine for thymine (GGT>CCA) known as the A140A 'silent' mutation since it does not change the amino acid (alanine) encoded for at that position. The severe UMN involvement and the fast progression of the disease may correlate with the MRI findings. It is also possible that the A140A mutation is not incidental; the mutated mRNA might be cytotoxic.
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| 47. |
- Byström, Roberth, et al.
(författare)
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SOD1 mutations targeting surface hydrogen bonds promote ALS without reducing apo-state stability
- 2010
-
Ingår i: Journal of Biological Chemistry. - : The American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 285:25, s. 19544-52
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Tidskriftsartikel (refereegranskat)abstract
- In good accord with the protein-aggregation hypothesis for neurodegenerative diseases, ALS-associated SOD1 mutations are found to reduce structural stability or net repulsive charge. Moreover there are weak indications that the ALS disease progression rate is correlated with the degree of mutational impact on the apo-SOD1 structure. A bottleneck for obtaining more conclusive information about these structure-disease relationships, however, is the large intrinsic variability in patient survival times and insufficient disease statistics for the majority of ALS-provoking mutations. As an alternative test of the structure-disease relationship we focus here on the SOD1 mutations that appear to be outliers in the data set. The results identify several ALS-provoking mutations whose only effect on apo SOD1 is the elimination or introduction of a single charge, i.e., D76V/Y, D101N and N139D/K. The thermodynamic stability and folding behaviour of these mutants are indistinguishable from the wildtype control. Moreover, D101N is an outlier in the plot of stability loss vs. patient survival time by having rapid disease progression. Common to the identified mutations is that they truncate conserved salt-links and/or H-bond networks in the functional loops IV or VII. The results show that the local impact of ALS-associated mutations on the SOD1 molecule can sometimes overrun their global effects on apo-state stability and net repulsive charge, and point at the analysis of property outliers as an efficient strategy for mapping out new ALS-provoking features.
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| 48. |
- Byström, Roberth, et al.
(författare)
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SOD1 Mutations Targeting Surface Hydrogen Bonds Promote Amyotrophic Lateral Sclerosis without Reducing Apo-state Stability
- 2010
-
Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 285:25, s. 19544-19552
-
Tidskriftsartikel (refereegranskat)abstract
- In good accord with the protein aggregation hypothesis for neurodegenerative diseases, ALS-associated SOD1 mutations are found to reduce structural stability or net repulsive charge. Moreover there are weak indications that the ALS disease progression rate is correlated with the degree of mutational impact on the apoSOD1 structure. A bottleneck for obtaining more conclusive information about these structure-disease relationships, however, is the large intrinsic variability in patient survival times and insufficient disease statistics for the majority of ALS- provoking mutations. As an alternative test of the structure- disease relationship we focus here on the SOD1 mutations that appear to be outliers in the data set. The results identify several ALS- provoking mutations whose only effect on apoSOD1 is the elimination or introduction of a single charge, i.e. D76V/Y, D101N, and N139D/K. The thermodynamic stability and folding behavior of these mutants are indistinguishable from the wild-type control. Moreover, D101N is an outlier in the plot of stability loss versus patient survival time by having rapid disease progression. Commonto the identified mutations is that they truncate conserved salt-links and/or H-bond networks in the functional loops IV or VII. The results show that the local impact of ALS- associated mutations on the SOD1 molecule can sometimes overrun their global effects on apo-state stability and net repulsive charge, and point at the analysis of property outliers as an efficient strategy for mapping out new ALS- provoking features.
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| 49. |
- Corcia, Philippe, et al.
(författare)
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Homozygous SMN2 deletion is a protective factor in the Swedish ALS population
- 2012
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 20:5, s. 588-591
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal survival motor neuron 1 (SMN1)-copy number has been associated with an increased risk of amyotrophic lateral sclerosis (ALS) in French and Dutch population studies. The aim of this study was to determine whether SMN gene copy number increases the risk of ALS or modulates its phenotype in a cohort of Swedish sporadic ALS (SALS) patients. In all, 502 Swedes with SALS and 502 Swedish controls matched for gender and age were enrolled. SMN1 and SMN2 gene copy numbers were studied by a semi-quantitative PCR method. A genotype-phenotype comparison was performed in order to determine whether SMN genes modulate the phenotype of ALS. The results were also compared with our previously reported French cohort of ALS patients. There was no difference between Swedish patients and controls in the frequency of SMN1 and SMN2 copy numbers. The frequency of SMN1 gene copies differed significantly between the French and Swedish ALS populations. The duration of the disease was significantly longer in the Swedish cohort with homozygous deletions of SMN2 when compared with the French cohort. Abnormal SMN1 gene copy number cannot be considered as a universal genetic susceptibility factor for SALS and this result underlines the importance of reproducing association gene studies in groups from different origins. We also suggest that SMN2 gene copy number might have different effects on ALS progression in disparate human populations. European Journal of Human Genetics (2012) 20, 588-591; doi:10.1038/ejhg.2011.255; published online 25 January 2012
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| 50. |
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