| 1. |
- 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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| 2. |
- 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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| 3. |
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| 4. |
- De Carvalho, Mamede, et al.
(författare)
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International Survey of ALS Experts about Critical Questions for Assessing Patients with ALS
- 2017
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis. - 2167-8421 .- 2167-9223. ; 18:7-8, s. 505-510
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To define an applicable dataset for ALS patient registries we weighted specific clinical items as scored by worldwide ALS experts.Methods: Sixty participants were invited based on relevant clinical work, publications and personal acquaintance. They rated 160 clinical items consensually agreed by the members of our project, incorporating specialists from five European Centres. Scoring scheme was defined as: 1 - essential; 2 - important; 3 - not very important. A mixed effect model was applied to rank items and to find possible correlations with geographical region (Europe vs. outside Europe).Results: We received 40 responses, 20 from Europe and 20 from outside; 42/160 data were scored as essential by >50% of the respondents, including: date of birth, gender, date of disease onset, date of diagnosis, ethnicity, region of onset, predominant upper neuron (UMN) or lower motor neuron (LMN) impairment, proximal versus distal weakness, respiratory symptoms, dysarthria, weight loss, signs of LMN/UMN involvement, emotional incontinence, cognitive changes, respiratory signs, neck weakness, body mass index, ALSFRS-R at entry, ALSFRS-R subscores at entry, timing and pattern of spreading and staging, electromyography, spirometry, MRI, CK level, riluzole intake, genetic background, history of physical exercise and previous and current main occupation. Four components were scored as non-relevant, including place of birth, blood pressure and pain at onset. There was no significant difference between regions (European vs. non-European countries).Conclusions: Our study identified a consensual set of clinical data with 42 specific items that can be used as a minimal data set for patient registers and for clinical trials.
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| 5. |
- de Carvalho, Mamede, et al.
(författare)
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Peripheral neuropathy in ALS : Phenotype association
- 2018
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Ingår i: Journal of the peripheral nervous system. - : John Wiley & Sons. - 1085-9489 .- 1529-8027. ; 23:4, s. 391-392
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 6. |
- Decarvalho, Mamede, et al.
(författare)
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Peripheral neuropathy in ALS : Phenotype association
- 2021
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X. ; 92:10, s. 1133-1134
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a rare and progressive neurodegenerative disease mainly affecting upper and lower motor neurons but also causing multisystem involvement, in particular, associated with cognitive changes. Minor sensory fibre dysfunction has been described in the past1 and confirmed in recent studies.2 In a multicentre study investigating a population of 88 patients with ALS, the ESTEEM group (a European Telematic Project for quality assurance within Clinical Neurophysiology) reported sensory polyneuropathy (PNP) in 12.5% of the patients, not influenced by age, disease duration and onset region.In this study, we aimed to readdress prevalence of and risk factors for PNP in a larger population of patients with ALS. A large number of variables, including gene mutations, were assessed.
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| 7. |
- Diekmann, Kristin, et al.
(författare)
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Impact of comorbidities and co-medication on disease onset and progression in a large German ALS patient group
- 2020
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Ingår i: Journal of Neurology. - : Springer. - 0340-5354 .- 1432-1459. ; 267:7, s. 2130-2141
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with loss of muscle function. The pathogenesis is still unclear and the heterogeneity of ALS phenotypes is huge. We investigated a large population of ALS patients and controls concerning comorbidities and medications to detect specific risk or protective factors regarding onset and progression of ALS.Methods: We investigated a cohort of 200 ALS patients pro- and retrospectively compared to a control group. For comparison of frequencies of comorbidities and medication intake, uni- and multivariate binary logistic regressions were performed. To analyze the influence of comorbidities and medication on the progression of ALS, we used linear regression analysis.Results: ALS patients showed a relevantly higher prevalence of strokes and depression compared to controls. Moreover, ALS patients reported relevantly more often regular physical activity and their BMI was lower. The coexistence of coronary heart disease was associated with a relevantly faster disease progression. Intake of contraceptives was relevantly higher in controls compared with ALS patients.Conclusions: Our results suggest stroke, lower BMI, and regular physical activity as risk factors for ALS. Strokes could be a possible trigger of the pathogenetic pathway of ALS and the lower BMI with consecutively lower rate of hyperlipidemia supports the hypothesis of premorbid hypermetabolism in ALS patients. Coexistence of coronary heart disease possibly has a negative influence on respiratory involvement. Contraceptives could be beneficial due to a protective effect of estrogen. Information on influencing factors can help to elucidate the pathogenesis of ALS or provide approaches for possible therapeutic options.
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| 8. |
- Gromicho, Marta, et al.
(författare)
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Motor neuron disease beginning with frontotemporal dementia : clinical features and progression
- 2021
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis. - 2167-8421 .- 2167-9223. ; 22:7-8, s. 508-516
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To study disease characteristics, progression and outcome in a group of motor neuron disease (MND) patients beginning with frontotemporal dementia (FTD) by comparing them with patients with the typical motor-onset.Methods: 849 patients recruited from tertiary centers were studied according to FTD-onset and motor-onset. We studied clinical data, functional decline and survival.Results: Twenty six patients (3.1%) had FTD-onset of whom seven (26.9%) had coincident motor dysfunction. In those with isolated FTD-onset, motor symptoms developed after a median of 12 months (IQR: 4-18). FTD-onset patients were older at presentation; the bulbar-region was more frequently first affected than in the motor-onset group; there was a predominant upper motor neuron (UMN) phenotype; fasciculations were less common than in motor onset disease but facial and upper limb apraxia was more frequent; as well as ALS and FTD familial history. No differences were observed for gender, frequency of C9orf72 hexanucleotide repeat expansion, family history of Alzheimer's and Parkinson's diseases, median delay from motor symptoms to diagnosis, median ALSFRS-R rate of change, handedness, emotional lability, depression, weight loss, resting tremor, bradykinesia, sensory changes or neuropathy. Clinical and demographic features were similar between FTD-onset patients developing bulbar MND and bulbar-onset ALS patients. Once bulbar symptoms manifested functional progression and survival were similar to those of bulbar-onset ALS patients.Conclusions: MND patients with FTD-onset have a distinctive phenotype characterized by predominant UMN presentation and rapid progression to bulbar involvement. The main factor impacting functional decline and survival is the onset of bulbar dysfunction.
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| 9. |
- Kliest, Tessa, et al.
(författare)
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Clinical trials in pediatric ALS: a TRICALS feasibility study
- 2022
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis Group. - 2167-8421 .- 2167-9223. ; 23:7-8, s. 481-488
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.
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| 10. |
- Korner, Sonja, et al.
(författare)
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Influence of Environment and Lifestyle on Incidence and Progress of Amyotrophic Lateral Sclerosis in A German ALS Population
- 2019
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Ingår i: Aging and Disease. - Fort Worth : International Society on Aging & Disease. - 2152-5250. ; 10:2, s. 205-216
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease mainly affecting upper and lower motor neurons in the brain and spinal cord. Pathogenesis of ALS is still unclear, and a multifactorial etiology is presumed. The remarkable clinical heterogeneity between different phenotypes of ALS patients suggests that environmental and lifestyle factors could play a role in onset and progression of ALS. We analyzed a cohort of 117 ALS patients and 93 controls. ALS patients and controls were compared regarding physical activity, dietary habits, smoking, residential environment, potentially toxic environmental factors and profession before symptom onset and throughout the disease course. Data were collected by a personal interview. For statistical analysis descriptive statistics, statistical tests and analysis of variance were used. ALS patients and controls did not differ regarding smoking, diet and extent of physical training. No higher frequency of toxic influences could be detected in the ALS group. ALS patients lived in rural environment considerably more often than the control persons, but this was not associated with a higher percentage of occupation in agriculture. There was also a higher percentage of university graduates in the ALS group. Patients with bulbar onset were considerably more often born in an urban environment as compared to spinal onset. Apart from education and environment, ALS phenotypes did not differ in any investigated environmental or life-style factor. The rate of disease progression was not influenced by any of the investigated environmental and life-style factors. The present study could not identify any dietary habit, smoking, physical activity, occupational factor as well as toxic influences as risk factor or protective factor for onset or progression of ALS. Living in rural environment and higher education might be associated with higher incidence of ALS.
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