Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration最新文献

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A speech measure for early stratification of fast and slow progressors of bulbar amyotrophic lateral sclerosis: lip movement jitter 快速和缓慢进展的球肌萎缩性侧索硬化症早期分层的言语测量:唇运动抖动
IF 2.8 4区 医学
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Pub Date : 2019-11-07 DOI: 10.1080/21678421.2019.1681454
Panying Rong, Y. Yunusova, M. Eshghi, Hannah P. Rowe, Jordan R. Green
{"title":"A speech measure for early stratification of fast and slow progressors of bulbar amyotrophic lateral sclerosis: lip movement jitter","authors":"Panying Rong, Y. Yunusova, M. Eshghi, Hannah P. Rowe, Jordan R. Green","doi":"10.1080/21678421.2019.1681454","DOIUrl":"https://doi.org/10.1080/21678421.2019.1681454","url":null,"abstract":"Abstract Objective: To assess the utility of novel measures derived from a rapid syllable repetition task (i.e. oral dysdiadochokinesis [DDK]) in early stratification of fast and slow progressive bulbar amyotrophic lateral sclerosis (ALS) and prediction of bulbar disease progression rate. Methods: Fifty-four individuals with ALS were tracked longitudinally on their oral DDK and global bulbar/speech performance (i.e. bulbar subscore on the ALS Functional Rating Scale-Revised [ALSFRS-R]; articulation rate during passage reading) for a four-month average duration. Based on the bulbar deterioration rate over the tracked period, the participants were stratified as 14 fast bulbar progressors and 40 slow bulbar progressors using a posteriori classification approach. To determine if oral DDK performance predicts the differential bulbar disease progression trajectories in these individuals during the early stages of the tracked period (prior to significant bulbar/speech signs), twenty-two measures of lip motor performance in an oral DDK task were derived to (1) differentiate fast and slow bulbar progressors using the Receiver Operating Characteristic analysis and (2) predict bulbar disease progression rates across all individuals using linear regressions. Results: Movement jitter, a measure of temporal variability of alternating lip movement during DDK, showed 80% sensitivity and 95% specificity in differentiating fast and slow bulbar progressors early in the disease, and outperformed the ALSFRS-R bulbar subscore and articulation rate. Movement jitter also predicted bulbar disease progression rates across participants. Conclusion: Findings provided preliminary validation of the clinical value of movement jitter during oral DDK in patient stratification and bulbar disease prognosis.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"21 1","pages":"34 - 41"},"PeriodicalIF":2.8,"publicationDate":"2019-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1681454","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46718949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 18
Theme 7 Pre-clinical therapeutic strategies. 主题7临床前治疗策略
IF 2.5 4区 医学
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Pub Date : 2019-11-01 DOI: 10.1080/21678421.2019.1646995
Vittoria Lombardi, Daniele Carassiti, Gavin Giovannoni, Ching-Hua Lu, Rocco Adiutori, Andrea Malaspina
{"title":"Theme 7 Pre-clinical therapeutic strategies.","authors":"Vittoria Lombardi, Daniele Carassiti, Gavin Giovannoni, Ching-Hua Lu, Rocco Adiutori, Andrea Malaspina","doi":"10.1080/21678421.2019.1646995","DOIUrl":"10.1080/21678421.2019.1646995","url":null,"abstract":"<p><p>The rise of neurodegenerative disorders (NDD) in the ageing population is increasing demand on already stretched Health Services and is a major financial burden for society (1). The development of tools for early diagnosis is one of the responses to this problem (2). Cerebrospinal fluid (CSF) is the main repository of by-products of neuronal destruction (3); as serial lumbar punctures to procure CSF may be impractical in advanced patients (4), blood may represent the ideal source to track any meaningful disease signal of neurodegeneration.High-costs and low energy efficiency have pushed alternative means of samples collection and storage. Noviplex dried plasma spot (Np-DPS) and dried blood spot (DBS) on filter paper can be a remote, quick and inexpensive way of obtaining blood microsamples for the measurement of a large number of analytes in non-hospitalized, public health settings (5).We have used commercially-available and highly sensitive immunodetection assays (6) to test neurofilament light chain (Nf-L) expression in elute from DBS and from Np-DPS and compared these to standard Nf-L plasma measurement of healthy controls and patients with amyotrophic lateral sclerosis (ALS).We show that DBS and Np-DP cards can be used for remote blood collection and measurement of Nf-L. Nf-L measurement using elute from Noviplex DPS cards is equivalent to that obtained in plasma from the same blood samples, while levels of the same analyte in DBS elute are different, but provide discrimination between controls and ALS patients. Normalization using known loading protein concentration may also be needed for DBS analysis to adjust for the chromatographic effect of retained haemoglobin in the spot elute. Conversely, a simple elution step is required for Np-DPS, which reconstitutes a test fluid which is indistinguishable from plasma originated by conventional blood processing.</p>","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"20 1","pages":"217-245"},"PeriodicalIF":2.5,"publicationDate":"2019-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45879783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Neurofilaments in pre-symptomatic ALS and the impact of genotype. 症状前肌萎缩侧索硬化症的神经丝及基因型的影响
IF 2.5 4区 医学
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Pub Date : 2019-11-01 Epub Date: 2019-08-21 DOI: 10.1080/21678421.2019.1646769
Michael Benatar, Joanne Wuu, Vittoria Lombardi, Andreas Jeromin, Robert Bowser, Peter M Andersen, Andrea Malaspina
{"title":"Neurofilaments in pre-symptomatic ALS and the impact of genotype.","authors":"Michael Benatar, Joanne Wuu, Vittoria Lombardi, Andreas Jeromin, Robert Bowser, Peter M Andersen, Andrea Malaspina","doi":"10.1080/21678421.2019.1646769","DOIUrl":"10.1080/21678421.2019.1646769","url":null,"abstract":"<p><p><i>Objective</i>. To evaluate serum and cerebrospinal fluid (CSF) levels of phosphorylated neurofilament heavy (pNfH), and to compare these to levels of neurofilament light (NfL), as biomarkers of pre-symptomatic ALS. <i>Design</i>. The study population includes 34 controls, 79 individuals at-risk for ALS, 22 ALS patients, and 14 phenoconverters. At-risk individuals are enrolled through <i>Pre-Symptomatic Familial ALS</i> (<i>Pre-fALS</i>), a longitudinal natural history and biomarker study of individuals who are carriers of any ALS-associated gene mutation, but who demonstrate no clinical evidence of disease at the time of enrollment. pNfH and NfL in serum and CSF were quantified using established enzyme-linked immunosorbent assays. <i>Results</i>. There is a longitudinal increase in serum pNfH in advance of the emergence of clinically manifest ALS. A similar pattern is observed for NfL, but with the absolute levels also frequently exceeding a normative threshold. Although CSF data are more sparse, similar patterns are observed for both neurofilaments, with absolute levels exceeding a normative threshold prior to phenoconversion. In serum, these changes are observed in the 6-12 months prior to disease among <i>SOD1</i> A4V mutation carriers, and as far back as 2 and 3.5 years, respectively, in individuals with a <i>FUS</i> c.521del6 mutation and a <i>C9ORF72</i> hexanucleotide repeat expansion. <i>Conclusions</i>. Serum and CSF pNfH increase prior to phenoconversion. In CSF, the temporal course of these changes is similar to NfL. In serum, however, pNfH is less sensitive to pre-symptomatic disease than NfL. The duration of pre-symptomatic disease, as defined by changes in neurofilaments, may vary depending on underlying genotype.</p>","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"20 1","pages":"538-548"},"PeriodicalIF":2.5,"publicationDate":"2019-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47764921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Table of Contents - Poster Communications 目录-海报通讯
IF 2.8 4区 医学
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Pub Date : 2019-10-31 DOI: 10.1080/21678421.2019.1647011
{"title":"Table of Contents - Poster Communications","authors":"","doi":"10.1080/21678421.2019.1647011","DOIUrl":"https://doi.org/10.1080/21678421.2019.1647011","url":null,"abstract":"","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"20 1","pages":"100 - 100"},"PeriodicalIF":2.8,"publicationDate":"2019-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1647011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45205238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Theme 5 Human cell biology and pathology 主题5:人类细胞生物学和病理学
IF 2.8 4区 医学
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Pub Date : 2019-10-31 DOI: 10.1080/21678421.2019.1646993
Anne Gieseler, Reyk Hillert, Andreas Krusche, K. Zacher
{"title":"Theme 5 Human cell biology and pathology","authors":"Anne Gieseler, Reyk Hillert, Andreas Krusche, K. Zacher","doi":"10.1080/21678421.2019.1646993","DOIUrl":"https://doi.org/10.1080/21678421.2019.1646993","url":null,"abstract":"Background: The delay from onset of the first symptoms to a definite ALS diagnosis depends also on the elusiveness of the initial clinical manifestations. The lack of disease-specific biomarkers to detect early pathology when ALS is supposed complicates the situation. This latency reduces the therapeutic time frame, in which neuron-rescuing strategies exert their greatest chance to work. Various biomarkers are currently promised, but none of them are specific enough to allow monitoring of disease progression. This, as well as the heterogeneity of the disease concerning clinical onset pattern and survival rates, makes difficult the correct stratification of patients into clinical trials, masking the potential positive outcome in some patients.Objective: Our main objective is to establish and test an early diagnostic tool based on microscopic immune cell monitoring of ALS patients' blood samples by using the Toponome Imaging System (TIS).Methods: TIS is based on automatically controlled microscopic device involving conjugated dye-tag incubation, protein-tag-dye-imaging, and tag-dye bleaching (1). This leads to the collection of at least 21 cycle images of fixated peripheral blood mononuclear cells (PBMCs) isolated from freshly drawn blood of ALS patients and healthy \"control\" donors. Resulting data sets contain combinatorial molecular information about the spatial protein network, called toponome. The PBMC toponome architectures are quantitatively analyzed as a threshold-binary code with 1 = protein is present and 0 = protein is absent.Results: Preliminary screening data of PBMCs from 4 ALS patients reveal a subpopulation of lymphocytes expressing a specific surface protein pattern, called \"ALS toponome\". These aberrant T cells could not be found in blood samples of controls. We observe that the number of these cells correlate with the ALS progression rate of patients, supporting the conclusion that these cells may be causal for the disease.Discussion and conclusion: Although these findings open up a potential strategy to detect early ALS disease and to monitor disease progression, a statistical analysis with many more patients, as well as data based differentiation to other neurodegenerative diseases, is mandatory. A clinical trial initiated by our faceALS foundation with at least 60 patients classified in three subsets (1. control, 2. ALS, and 3. Multiple Sclerosis (MS)) and in close cooperation with leading ALS centres in Germany is still in progress. The detection of specific and/or aberrant immune cells in blood samples of ALS patients may provide a key to understand disease onset and progression, could be used for the \"staging\" of disease, and contribute to effective therapy options.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"20 1","pages":"188 - 205"},"PeriodicalIF":2.8,"publicationDate":"2019-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1646993","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48275249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Theme 2 Genetics and genomics 主题2遗传学和基因组学
IF 2.8 4区 医学
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Pub Date : 2019-10-31 DOI: 10.1080/21678421.2019.1646990
J. Roggenbuck, Carly Doyle, Tara Lincoln, J. Glass
{"title":"Theme 2 Genetics and genomics","authors":"J. Roggenbuck, Carly Doyle, Tara Lincoln, J. Glass","doi":"10.1080/21678421.2019.1646990","DOIUrl":"https://doi.org/10.1080/21678421.2019.1646990","url":null,"abstract":"Background: A genetic basis is found in ∼70% of familial and ∼15% of sporadic ALS, in research cohorts. Clinical trials of gene-targeted therapies are underway, heralding a new era of personalized medicine in ALS treatment. However, ALS management guidelines do not include recommendations for the offer of genetic testing. Many persons with ALS who desire genetic testing are not currently offered it, and the yield of genetic testing in clinic-based ALS populations is unknown. The ALS GAP program, sponsored by the Northeast ALS (NEALS) Consortium, provides free genetic testing for patients with ALS who have a family history of ALS or dementia. We report genetic testing outcomes in the first 142 patients tested in the \u2028program.Objectives: 1) To create a pilot ALS genetic testing program for NEALS clinics, 2) To study the rate of ALS gene identification in a US clinic-based populationMethods: Persons with ALS and a family history of ALS (fALS) or dementia (dALS) who receive care at a US NEALS clinic are eligible for testing. Patients classified as fALS (having a positive family history of ALS in a 1st, 2nd, or 3rd degree relative) are eligible for C9orf72 testing, with the option to reflex to a 5 gene (SOD1, FUS, TARDBP, TBK1, VCP) panel. Patients classified as dALS (having a positive family history of dementia of any type in a 1st or 2nd degree relative) are eligible for C9orf72 testing only.Results: Currently, 29.5% (34/115) of US NEALS clinics have participated in the program. Of 142 patients who have completed testing to date, 78 (54.9%) were classified as fALS and 64 (45.1%) as dALS. Among fALS cases, 42/78 (53.9%) tested positive, including 32/78 (41%) with a C9orf72 repeat expansion, and 10/78 (12.8%) with other pathogenic or likely pathogenic variants in SOD, FUS, TARDP or VCP. Variants of uncertain significance (VUS) in FUS were identified in 2/78 (2.6%). Among dALS cases, 12/60 (20%) tested positive for C9orf72.Discussion and conclusions: Participation in ALS-GAP indicates significant clinician and patient interest in ALS genetic testing. This program addresses several current barriers to testing access, including cost, identifying appropriate candidates for testing, and appropriate test selection. Although 38% of patients who participated in the program have thus far received a genetic diagnosis, our testing outcome data suggests that the gene identification rate in fALS cases may be lower in clinic-based patients than in research cohorts, particularly for genes other than C9orf72. This program may serve as a model for the practice of ALS genetic testing in the clinic setting. Consistent, equitable testing policies, as well as an accurate understanding of the genetic profile of clinic-based ALS populations, are needed as gene-targeted therapies reach patient care.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"20 1","pages":"114 - 134"},"PeriodicalIF":2.8,"publicationDate":"2019-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1646990","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42241331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Theme 6 Tissue biomarkers 主题6组织生物标志物
IF 2.8 4区 医学
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Pub Date : 2019-10-31 DOI: 10.1080/21678421.2019.1646994
Karen R. Garnaas, J. Kittelsrud, M. Behnke
{"title":"Theme 6 Tissue biomarkers","authors":"Karen R. Garnaas, J. Kittelsrud, M. Behnke","doi":"10.1080/21678421.2019.1646994","DOIUrl":"https://doi.org/10.1080/21678421.2019.1646994","url":null,"abstract":"Background: Glutamate excitotoxicity is a longstanding hypothesis in the pathophysiology of ALS. Prior studies have demonstrated increased plasma glutamate levels in ALS patients, which suggest a systemic defect in glutamate metabolism (1). The most abundant amino acid consumed in our diet is glutamate. Studies in healthy human subjects have demonstrated efficient metabolism of dietary glutamate via metabolism by enzymes present in the liver, gut lumen and residential gut bacteria. There is increasing evidence that the gut microbiota has significant CNS effects and intestinal dysbiosis has been found in the ALS transgenic SOD1G93A mouse model (2). If intestinal dysbiosis altered the prevalence of glutamine synthetase (GS) producing bacteria, dietary glutamate homeostasis could be impaired, leading to elevated plasma glutamate levels.Objectives: This study examined the degree of fluctuation in plasma glutamate levels seen with consumption of a protein shake in a cohort of ALS patients and family members from a single ALS center.Methods: Twenty six patients (87% of total cohort followed in the ALS center) underwent measurement of plasma amino acid analysis prior to and 1 hour following consumption of a 75 gm protein shake. A subset of 16 patients went on to receive a probiotic with high GS activity and completed serial protein challenges and amino acid analysis during the study. Ten unaffected family members of ALS patients underwent a similar protein challenge. Glutamate Metabolism Dysfunction (GMD) was defined as >30 umol difference post-prandially compared to fasting, and graded as mild (>30-60), moderate (>60-90) or severe (>90).Results: At baseline, 65.4% (17/26) ALS patients screened were GMD positive, compared to 30% (3/10) of tested family members. The severity of GMD in ALS patients was 41% mild, 29% moderate, 29% severe with only mild severity identified in family members. In the six month treatment phase, 75% (6/8) of patients with stable or improving GMD status saw significant improvements in their ALSFRS-R rate of decline, while 71.4% (5/7) with worsening or remaining severe GMD status experienced worsening of their rate of progression.Discussion and conclusions: Although limited by small sample size, this study does represent an excellent sampling within a single ALS center and is the first of its kind to investigate whether impairment in dietary glutamate metabolism exists in ALS patients. If validated in a larger ALS population, detection of glutamate metabolism dysfunction (GMD) could represent a novel biomarker linked to a potential therapeutic target in ALS patients. Planned microbiome analysis will also help in validating this hypothesis.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"20 1","pages":"206 - 216"},"PeriodicalIF":2.8,"publicationDate":"2019-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1646994","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46534891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Theme 13 Clinical management and support 主题13临床管理和支持
IF 2.8 4区 医学
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Pub Date : 2019-10-31 DOI: 10.1080/21678421.2019.1647002
A. Crook, A. Hogden, V. Mumford, I. Blair, K. Williams, D. Rowe
{"title":"Theme 13 Clinical management and support","authors":"A. Crook, A. Hogden, V. Mumford, I. Blair, K. Williams, D. Rowe","doi":"10.1080/21678421.2019.1647002","DOIUrl":"https://doi.org/10.1080/21678421.2019.1647002","url":null,"abstract":"Background: Pathogenic variants in ALS genes are known to be present in up to 70% of familial and 10% of apparently sporadic ALS cases, and can be associated with risks for ALS only, or risks for other neurodegenerative diseases (eg. frontotemporal dementia). While there are no changes to medical management for patients confirmed as pathogenic variant carriers, genetic testing may be important for future drug trials. Confirmation of a pathogenic variant also provides relatives with the opportunity to consider predictive and/or reproductive genetic testing. Genetic counselling is an important aspect of testing decision-making as it enables individuals to make informed decisions about genetic testing while minimising adverse psychological, ethical and legal outcomes. Few studies have explored how individuals decide whether to pursue testing, nor the needs and experiences of familial ALS families.Objective: To identify factors that influence patient and family member decision-making about genetic testing for ALS genes, assess the impact of familial disease on the patient and their family, and identify information and support needs.Methods: In-depth, semi-structured interviews with individuals from Australian ALS families with known pathogenic gene variants explored experiences of familial ALS, and factors that influenced genetic testing decision-making. Interviews were analysed using an inductive approach.Results: Thirty-four individuals from 24 families were interviewed and included patients (n = 4), spouses (n = 4), and asymptomatic at-risk relatives (n = 26). Life stage, experience of disease, costs, research opportunities, and attitudes to familial ALS and/or reproductive options influenced decision-making. Some patients and relatives experienced difficulty gaining accurate information from their health professionals about the costs and implications of genetic counselling or testing, resulting in a reluctance to proceed.Discussion and conclusion: This study provides new insight into the Australian experience of genetic testing and counselling for familial ALS. It highlights the need to work together with other health professionals to ensure the complexities of genetic testing decision-making, and referral pathways are better understood.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"79 1","pages":"327 - 347"},"PeriodicalIF":2.8,"publicationDate":"2019-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79310996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Platform Communications: Abstract Book - 30th International Symposium on ALS/MND (Complete printable file) 平台通讯:摘要书-第30届ALS/MND国际研讨会(完整可打印文件)
IF 2.8 4区 医学
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Pub Date : 2019-10-31 DOI: 10.1080/21678421.2019.1646546
O. Hardiman, Sharon Abrahams, A. Al-Chalabi
{"title":"Platform Communications: Abstract Book - 30th International Symposium on ALS/MND (Complete printable file)","authors":"O. Hardiman, Sharon Abrahams, A. Al-Chalabi","doi":"10.1080/21678421.2019.1646546","DOIUrl":"https://doi.org/10.1080/21678421.2019.1646546","url":null,"abstract":"","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"20 1","pages":"1 - 99"},"PeriodicalIF":2.8,"publicationDate":"2019-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1646546","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48491985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 4
Theme 4 In vivo experimental models 主题4体内实验模型
IF 2.8 4区 医学
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Pub Date : 2019-10-31 DOI: 10.1080/21678421.2019.1646992
A. Chudinova, M. Rossel, A. Vergunst, Gwendal Le-Masson, W. Camu, C. Raoul, S. Lumbroso, K. Mouzat
{"title":"Theme 4 In vivo experimental models","authors":"A. Chudinova, M. Rossel, A. Vergunst, Gwendal Le-Masson, W. Camu, C. Raoul, S. Lumbroso, K. Mouzat","doi":"10.1080/21678421.2019.1646992","DOIUrl":"https://doi.org/10.1080/21678421.2019.1646992","url":null,"abstract":"Background: In 90% of Amyotrophic Lateral Sclerosis (ALS) cases, the disease is sporadic, the remaining 10% being familial. Many genes have been associated with the disease. The use of next generation sequencing has allowed increasing the number of genes analysed in routine diagnostics. However, this increase raises the issue of genetic variants interpretation within a growing number of ALS-associated-genes. Variant classification is based on a combinatory analysis of multiple factors. Among them, functional analyses provide strong arguments on pathogenicity interpretation.Objectives: We developed a simple animal model, the Zebrafish, for the functional analysis of candidate variants pathogenicity identified by routine genetic testing.Methods: Transient overexpression of different ALS associated genetic variants has been performed by mRNA injection in 1-cell stage zebrafish eggs. Validation of protein overexpression has been done by western blot. Embryos mortality, developmental delay and morphological abnormalities have been assessed within the first two days of development. Cellular phenotype has been investigated by the analysis of axonal length of 2-days old larvae with confocal microscopy. Motor phenotype of 5-days old larvae has been explored by touched-evoked response assay.Results: The model has been validated by the analysis of well-described ALS mutations, SOD1-Gly93Ala and OPTN Glu478Gly. Overexpression of this mutated protein was shown to provoke a shortening of axons and a premature axonal branching, as well as an impairment of motor performances as expected. We did not observe these aberrations in SOD1-WT injected fishes. Two candidate variants observed in ALS-patients have been explored with our model: SOD1 NM_000454.4:c.400_402del, p.Glu134del and OPTN NM_021980.4:c.1475T > G, p. Leu492Arg. Overexpression of both variants induced morphological abnormalities and motor impairment, suggesting a pathogenic involvement of these variants in ALS-patients.Discussion and conclusions: We developed for the first time a simple animal model, the Zebrafish, useful for the functional analysis of variant pathogenicity in order to assist ALS molecular diagnosis. Our model has been used to assess the pathogenicity of SOD1 and OPTN candidate variants, allowing to improve genetic testing interpretation.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"20 1","pages":"160 - 187"},"PeriodicalIF":2.8,"publicationDate":"2019-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1646992","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44898851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
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