| 1. |
- Oeckl, Patrick, et al.
(författare)
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Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase
- 2019
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X. ; 90:1, s. 4-10
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the role of neuroinflammation in asymptomatic and symptomatic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mutation carriers.Methods: The neuroinflammatory markers chitotriosidase 1 (CHIT1), YKL-40 and glial fibrillary acidic protein (GFAP) were measured in cerebrospinal fluid (CSF) and blood samples from asymptomatic and symptomatic ALS/FTD mutation carriers, sporadic cases and controls by ELISA.Results: CSF levels of CHIT1, YKL-40 and GFAP were unaffected in asymptomatic mutation carriers (n=16). CHIT1 and YKL-40 were increased in gALS (p<0.001, n=65) whereas GFAP was not affected. Patients with ALS carrying a CHIT1 polymorphism had lower CHIT1 concentrations in CSF (-80%) whereas this polymorphism had no influence on disease severity. In gFTD (n=23), increased YKL-40 and GFAP were observed (p<0.05), whereas CHIT1 was nearly not affected. The same profile as in gALS and gFTD was observed in sALS (n=64/70) and sFTD (n=20/26). CSF and blood concentrations correlated moderately (CHIT1, r=0.51) to weak (YKL-40, r=0.30, GFAP, r=0.39). Blood concentrations of these three markers were not significantly altered in any of the groups except CHIT1 in gALS of the Ulm cohort (p<0.05).Conclusion: Our data indicate that neuroinflammation is linked to the symptomatic phase of ALS/FTD and shows a similar pattern in sporadic and genetic cases. ALS and FTD are characterised by a different neuroinflammatory profile, which might be one driver of the diverse presentations of the ALS/FTD syndrome.
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| 2. |
- Steinacker, Petra, et al.
(författare)
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Neurofilaments in the diagnosis of motoneuron diseases : a prospective study on 455 patients
- 2016
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 87:1, s. 12-20
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Biomarkers for the diagnosis of motoneuron diseases (MND) are urgently needed to improve the diagnostic pathway, patient stratification and monitoring. The aim of this study was to validate candidate markers for MND in cerebrospinal fluid (CSF) and specify cut-offs based on large patient cohorts by especially considering patients who were seen under the initial differential diagnosis (MND mimics). Methods In a prospective study, we investigated CSF of 455 patients for neurofilament light chain (NfL), phosphorylated heavy chain (pNfH), tau protein (Tau) and phospho-tau protein (pTau). Analysed cohorts included patients with apparently sporadic and familial amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) (MND, n=253), MND mimics (n=85) and neurological control groups. Cut-off values were specified, and diagnostic performance and correlation with progression were analysed. Results Nfs were significantly higher in the MND group compared to the control groups, whereas Tau and pTau did not differ. At a cut-off level of 2200 pg/mL for NfL, a 77% diagnostic sensitivity (CI 71% to 82%), 85% specificity (CI 79% to 90%) and 87% positive predictive value (PPV) (CI 81% to 91%) were achieved. For pNfH, we calculated 83% sensitivity (CI 78% to 88%), 77% specificity (CI 71% to 83%) and 82% PPV (CI 77% to 86%) at 560 pg/mL. There were no significant differences between sporadic and genetic ALS or PLS. Nf levels were elevated at early disease stage, and correlated moderately with MND progression and duration. Conclusions Neurofilaments in CSF have a high relevance for the differential diagnosis of MNDs and should be included in the diagnostic work-up of patients. Their value as prognostic markers should be investigated further.
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| 3. |
- Weydt, Patrick, et al.
(författare)
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Neurofilament Levels as Biomarkers in Asymptomatic and Symptomatic Familial Amyotrophic Lateral Sclerosis
- 2016
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 79:1, s. 152-158
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Tidskriftsartikel (refereegranskat)abstract
- Neurofilaments are elevated in the cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients. However, timing of this increase is unknown. To characterize the premanifest disease phase, we performed a cross-sectional study on asymptomatic (n=12) and symptomatic (n=64) ALS mutation carriers and family controls (n=19). Neurofilaments NF-L (neurofilament-light chain) and pNF-H (phosphorylated neurofilament-heavy chain) are normal before symptom onset and increased by at least an order of magnitude at early symptom onset in CSF (pNF-H) or serum and CSF (NF-L). Thus, blood and CSF neurofilament levels are linked to the symptomatic phase of ALS and might serve as objective markers of structural damage to the nervous system.
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| 4. |
- Al-Chalabi, Ammar, et al.
(författare)
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July 2017 ENCALS statement on edaravone
- 2017
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : TAYLOR & FRANCIS LTD. - 2167-8421 .- 2167-9223. ; 18:7-8, s. 471-474
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Tidskriftsartikel (refereegranskat)abstract
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| 5. |
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| 6. |
- Brenner, David, et al.
(författare)
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Hot-spot KIF5A mutations cause familial ALS
- 2018
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Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 141, s. 688-697
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Tidskriftsartikel (refereegranskat)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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| 7. |
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| 8. |
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| 9. |
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| 10. |
- Dorst, Johannes, et al.
(författare)
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Metabolic alterations precede neurofilament changes in presymptomatic ALS gene carriers
- 2023
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 90
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Tidskriftsartikel (refereegranskat)abstract
- Background: The emergence of potentially effective new therapies for genetic forms of amyotrophic lateral sclerosis (ALS) necessitates the identification of biomarkers to facilitate early treatment, prior to the onset of motor symptoms. Here, we sought to investigate whether metabolic alterations are detectable in presymptomatic ALS gene mutation carriers, and whether such alterations precede neurofilament light chain (NfL) changes in serum.Methods: Between 02/2014 and 11/2021, we prospectively studied 60 presymptomatic ALS gene mutation carriers (40% male, age 48.7 ± 14.9; 28 C9orf72, 22 SOD1, 10 other) compared to 73 individuals from the same families (47% male, age 47.4 ± 12.9) without pathogenic mutations as controls. Bioimpedance analysis (BIA) and indirect calorimetry were performed, and Body Mass Index (BMI), Fat Mass (FM), Body Fat Percentage, Body Water (BW), Lean Body Mass (LBM), Extracellular Mass (ECM), Body Cell Mass (BCM), ECM/BCM ratio, Cells Percentage, Phase Angle, Resting Metabolic Rate (RMR), Metabolic Ratio (MR), and NfL were measured. Participants and evaluators were blinded regarding gene carrier status.Findings: Presymptomatic ALS gene carriers showed reduced LBM (p = 0.02), BCM (p = 0.004), Cells Percentage (p = 0.04), BW (p = 0.02), Phase Angle (p = 0.04), and increased ECM/BCM ratio (p = 0.04), consistently indicating a loss of metabolically active body cells. While in C9orf72 mutation carriers all tissue masses were reduced, only metabolically active tissue was affected in SOD1 mutation carriers. Unexpectedly, RMR (p = 0.009) and MR (p = 0.01) were lower in presymptomatic ALS gene carriers compared to non-carriers. NfL serum levels were similar in mutation carriers and non-carriers (p = 0.60).Interpretation: The observed metabolic phenomena might reflect reduced physical activity and/or preemptive, insufficient compensatory mechanisms to prepare for the later hypermetabolic state. As pre-symptomatic biomarkers we propose ECM/BCM ratio and Phase Angle for SOD1, and a 4-compartment affection in BIA for C9orf72 mutation carriers.
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| 11. |
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| 12. |
- Dupuis, Luc, et al.
(författare)
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Thermoregulation in amyotrophic lateral sclerosis
- 2018
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Ingår i: Handbook of Clinical Neurology. - 0072-9752 .- 2212-4152. ; 157, s. 749-760
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Bokkapitel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is the major adult-onset motor neuron disease, and is clinically, pathologically, and genetically associated with frontotemporal dementia, the second cause of dementia in the elderly. Here, we review the evidence linking thermoregulation and ALS. Indeed, while ALS is not classically associated with defective thermoregulatory function, its progression severely affects key brain regions controlling body temperature and impacts multiple sensors and effectors of this homeostatic function. Furthermore, animal models of ALS display disturbed thermoregulation as a consequence of disrupted energy homeostasis. All these lines of indirect evidence call for studies directly addressing the body temperature regulatory system, both as a potential biomarker and as a possible modifier of disease progression in ALS.
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| 13. |
- Eschbach, Judith, et al.
(författare)
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PGC-1 is a male-specific disease modifier of human and experimental amyotrophic lateral sclerosis
- 2013
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:17, s. 3477-3484
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a devastating, adult-onset neurodegenerative disorder of the upper and lower motor systems. It leads to paresis, muscle wasting and inevitably to death, typically within 35 years. However, disease onset and survival vary considerably ranging in extreme cases from a few months to several decades. The genetic and environmental factors underlying this variability are of great interest as potential therapeutic targets. In ALS, men are affected more often and have an earlier age of onset than women. This gender difference is recapitulated in transgenic rodent models, but no underlying mechanism has been elucidated. Here we report that SNPs in the brain-specific promoter region of the transcriptional co-activator PGC-1, a master regulator of metabolism, modulate age of onset and survival in two large and independent ALS populations and this occurs in a strictly male-specific manner. In complementary animal studies, we show that deficiency of full-length (FL) Pgc-1 leads to a significantly earlier age of onset and a borderline shortened survival in male, but not in female ALS-transgenic mice. In the animal model, FL Pgc-1-loss is associated with reduced mRNA levels of the trophic factor Vegf-A in males, but not in females. In summary, we indentify PGC-1 as a novel and clinically relevant disease modifier of human and experimental ALS and report a sex-dependent effect of PGC-1 in this neurodegenerative disorder.
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| 14. |
- Freischmidt, Axel, et al.
(författare)
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Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia
- 2015
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Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 18:5, s. 631-
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.
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| 15. |
- Freischmidt, Axel, et al.
(författare)
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Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers
- 2014
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 137:11, s. 2938-2950
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge about the nature of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis is largely lacking. It could not only pave the way for the discovery of valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained comprehensive expression profiles of microRNAs in the serum of patients with familial amyotrophic lateral sclerosis, asymptomatic mutation carriers and healthy control subjects. We observed a strikingly homogenous microRNA profile in patients with familial amyotrophic lateral sclerosis that was largely independent from the underlying disease gene. Moreover, we identified 24 significantly downregulated microRNAs in pre-manifest amyotrophic lateral sclerosis mutation carriers up to two decades or more before the estimated time window of disease onset; 91.7% of the downregulated microRNAs in mutation carriers overlapped with the patients with familial amyotrophic lateral sclerosis. Bioinformatic analysis revealed a consensus sequence motif present in the vast majority of downregulated microRNAs identified in this study. Our data thus suggest specific common denominators regarding molecular pathogenesis of different amyotrophic lateral sclerosis genes. We describe the earliest pathomolecular alterations in amyotrophic lateral sclerosis mutation carriers known to date, which provide a basis for the discovery of novel therapeutic targets and strongly argue for studies evaluating presymptomatic disease-modifying treatment in amyotrophic lateral sclerosis.
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| 16. |
- Gorges, Martin, et al.
(författare)
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Hypothalamic atrophy is related to body mass index and age at onset in amyotrophic lateral sclerosis
- 2017
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 88:12, s. 1033-1041
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Our objective was to study the hypothalamic volume in a cohort of patients with amyotrophic lateral sclerosis (ALS) including symptomatic and presymptomatic ALS mutation carriers.Methods: High-resolution three-dimensional T1-weighted MRI datasets from 251 patients with sporadic ALS, 19 symptomatic and 32 presymptomatic ALS mutation carriers and 112 healthy controls (HC) were retrospectivally registered for manual delineation of the hypothalamus. The volume of the hypothalamus, in total or subdivided, was normalised to the intracranial volume and adjusted to age. Correlation analyses were performed with clinical and metabolic outcomes. Pathologically defined ALS stages were determined in vivo by diffusion tensor imaging (DTI).Results: We observed a severe atrophy of the hypothalamus both in patients with sporadic ALS (-21.8%, p<0.0001) and symptomatic ALS mutation carriers (-13.4%, p<0.001). The atrophy in patients with sporadic ALS was observed in both the anterior (-27.6% p<0.0001) and the posterior parts of the hypothalamus (-17.7%, p<0.0001). Notably, this atrophy was also observed in presymptomatic ALS mutation carriers (-15.5%, p<0.001) and was unrelated to whole brain volume atrophy or disease stage as assessed using DTI or functional status. Hypothalamic volume was correlated with body mass index (BMI) in patients with sporadic ALS (p=0.0434, Ρ=+0.1579), and this correlation was much stronger in patients with familial ALS (fALS) (p=0.0060, Ρ=+0.6053). Anterior hypothalamic volume was correlated with age at onset, but not with survival after MRI.Conclusions: Hypothalamus is atrophied in ALS, even in premorbid stages, and correlates with BMI, especially in fALS. Decreased anterior hypothalamic volume is associated with earlier onset of disease.
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| 17. |
- Lulé, Dorothée E., et al.
(författare)
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Deficits in verbal fluency in presymptomatic C9orf72 mutation gene carriers-a developmental disorder
- 2020
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X. ; 91:11, s. 1195-1200
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Tidskriftsartikel (refereegranskat)abstract
- Background: A mutation in C9orf72 constitute a cross-link between amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). At clinical manifestation, both patient groups may present with either cognitive impairment of predominantly behaviour or language (in FTD) or motor dysfunctions (in ALS).Methods: In total, 36 non-symptomatic mutation carriers from ALS or FTD families were examined, including 21 subjects with C9orf72 and 15 with SOD1 mutations. Data were compared with 91 age-matched, education-matched and gender-matched healthy subjects (56 were first-degree relatives from ALS or FTD families, 35 with no known family history of ALS/FTD). MRI scanning for diffusion tensor imaging was performed to map fractional anisotropy (FA). Subjects performed an extensive neuropsychological assessment to address verbal fluency, language, executive, memory and visuospatial function. Measurements were repeated after 12 months.Results: C9orf72 expansion carriers performed significantly worse in verbal fluency and non-verbal memory and presented with distinct alterations in structural white matter integrity indicated by lower FA values in inferior and orbitofrontal cortical areas compared with carriers of SOD1 mutations or healthy subjects. Loss of structural integrity was associated with decreased verbal fluency performance. White matter alterations and cognitive performance showed no changes over 12 months in all subjects.Discussion: Reduced verbal fluency performance seems to be a distinct clinical feature of C9orf72 carriers before symptomatic disease onset without evidence for change over time in our cohort. The results support the emerging hypothesis of a general disorder in development in addition to neurodegeneration in C9orf72 carriers.
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| 18. |
- Mueller, Kathrin, et al.
(författare)
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Comprehensive analysis of the mutation spectrum in 301 German ALS families
- 2018
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X. ; 89:8, s. 817-827
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Recent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions.Methods Here we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families.Results 49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes.Conclusions We here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe.
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| 19. |
- Petersén, Åsa, et al.
(författare)
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The psychopharmacology of Huntington disease
- 2019
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Ingår i: Handbook of Clinical Neurology : Psychopharmacology of Neurologic Disease - Psychopharmacology of Neurologic Disease. ; 165, s. 179-189
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Bokkapitel (refereegranskat)abstract
- Huntington disease (HD) is a hereditary neurodegenerative disorder caused by an expanded cytosine–adenine–guanine triplet repeat in the huntingtin gene. The current diagnosis is based on the presence of typical motor signs in combination with a positive gene test. The motor onset of the disease is usually between 30 and 50 years of age, and the disease then progresses over around 20 more years. Nonmotor symptoms and signs such as cognitive decline, metabolic dysfunction, sleep disturbances, as well as psychiatric symptoms are common and can occur many years before motor onset. Psychiatric symptoms include irritability, apathy, depression, anxiety, and OCD. Although there exist no disease-modifying treatment, available pharmacologic drugs often offer significant symptom relief and improve quality of life. Today, there are only two drugs that are approved by the US Food and Drug Association for the treatment of HD. These are the dopamine-depleting drugs tetrabenazine and deutetrabenazine that both target motor symptoms. The current status of best clinical practice for HD is based on expert opinions as well as evidence and/or experience of treating similar symptoms in other conditions. In this chapter, we provide an overview of the complex clinical manifestations of HD and the commonly used psychopharmacologic treatments.
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| 20. |
- Rosenbohm, Angela, et al.
(författare)
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Can lesions to the motor cortex induce amyotrophic lateral sclerosis?
- 2014
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Ingår i: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 261:2, s. 283-290
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Tidskriftsartikel (refereegranskat)abstract
- A recent staging effort for amyotrophic lateral sclerosis (ALS) has demonstrated that the TDP-43 neuropathology may initiate focally in the motor cortex in the majority of patients. We searched our data bank for patients with lesions of the motor cortex which preceded disease onset. We performed a search of our patient- and MRI-data bank and screened 1,835 patients with amyotrophic lateral sclerosis for frontal lobe/motor cortex lesions. We found 18 patients with definite ALS who had documented and defined lesions of the motor cortex, which preceded the initial ALS symptoms by 8-42 years. In the vast majority (15/18) of the patients, the onset of ALS was closely related to the focal lesion since it started in a body region reflecting the damaged cortical area. The findings suggest that initial lesions to the motor cortex may be a contributing initiating factor in some patients with ALS or determine the site of onset in individuals pre-disposed to ALS.
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| 21. |
- Weydt, Patrick, et al.
(författare)
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Thermoregulatory disorders in Huntington disease
- 2018
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Ingår i: Handbook of Clinical Neurology. - 2212-4152 .- 0072-9752. ; 157, s. 761-775
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Bokkapitel (refereegranskat)abstract
- Huntington disease (HD) is a paradigmatic autosomal-dominant adult-onset neurodegenerative disease. Since the identification of an abnormal expansion of a trinucleotide repeat tract in the huntingtin gene as the underlying genetic defect, a broad range of transgenic animal models of the disease has become available and these have helped to unravel the relevant molecular pathways in unprecedented detail. Of note, some of the most informative of these models develop thermoregulatory defects such as hypothermia, problems with adaptive thermogenesis, and an altered circadian temperature rhythm. Both central, e.g., in the hypothalamus and peripheral, i.e., the brown adipose tissue and skeletal muscle, problems contribute to the phenotype. Importantly, these structures and pathways are also affected in human HD. Yet, currently the evidence for bona fide thermodysregulation in human HD patients remains anecdotal. This may be due to a lack of reliable tools for monitoring body temperature in an outpatient setting. Regardless, study of the temperature phenotype has contributed to the identification of unexpected molecular targets, such as the PGC-1α pathway.
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