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1. Senataxin mutations elicit motor neuron degeneration phenotypes and yield TDP-43 mislocalization in ALS4 mice and human patients

Author

Bennett, Craig L, Dastidar, Somasish G, Ling, Shuo-Chien, Malik, Bilal, Ashe, Travis, Wadhwa, Mandheer, Miller, Derek B, Lee, Changwoo, Mitchell, Matthew B, van Es, Michael A, Grunseich, Christopher, Chen, Yingzhang, Sopher, Bryce L, Greensmith, Linda, Cleveland, Don W, and La Spada, Albert R

Subjects
Biomedical and Clinical Sciences, Neurosciences, Neurodegenerative, ALS, Brain Disorders, Genetics, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Neurological, Amyotrophic Lateral Sclerosis, Animals, DNA Helicases, DNA-Binding Proteins, Female, Humans, Male, Mice, Motor Neurons, Multifunctional Enzymes, Nerve Degeneration, Phenotype, RNA Helicases, Amyotrophic lateral sclerosis, Senataxin, Transgenesis, Gene targeting, TDP-43, Nucleocytoplasmic transport, Ran, RanGAP1, Motor neuron, Neurodegeneration, Clinical Sciences, Neurology & Neurosurgery
Abstract

Amyotrophic lateral sclerosis type 4 (ALS4) is a rare, early-onset, autosomal dominant form of ALS, characterized by slow disease progression and sparing of respiratory musculature. Dominant, gain-of-function mutations in the senataxin gene (SETX) cause ALS4, but the mechanistic basis for motor neuron toxicity is unknown. SETX is a RNA-binding protein with a highly conserved helicase domain, but does not possess a low-complexity domain, making it unique among ALS-linked disease proteins. We derived ALS4 mouse models by expressing two different senataxin gene mutations (R2136H and L389S) via transgenesis and knock-in gene targeting. Both approaches yielded SETX mutant mice that develop neuromuscular phenotypes and motor neuron degeneration. Neuropathological characterization of SETX mice revealed nuclear clearing of TDP-43, accompanied by TDP-43 cytosolic mislocalization, consistent with the hallmark pathology observed in human ALS patients. Postmortem material from ALS4 patients exhibited TDP-43 mislocalization in spinal cord motor neurons, and motor neurons from SETX ALS4 mice displayed enhanced stress granule formation. Immunostaining analysis for nucleocytoplasmic transport proteins Ran and RanGAP1 uncovered nuclear membrane abnormalities in the motor neurons of SETX ALS4 mice, and nuclear import was delayed in SETX ALS4 cortical neurons, indicative of impaired nucleocytoplasmic trafficking. SETX ALS4 mice thus recapitulated ALS disease phenotypes in association with TDP-43 mislocalization and provided insight into the basis for TDP-43 histopathology, linking SETX dysfunction to common pathways of ALS motor neuron degeneration.

Published
2018

2. No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis

Author

Goris, An, van Setten, Jessica, Diekstra, Frank, Ripke, Stephan, Patsopoulos, Nikolaos A, Sawcer, Stephen J, van Es, Michael, Andersen, Peter M, Melki, Judith, Meininger, Vincent, Hardiman, Orla, Landers, John E, Brown, Robert H, Shatunov, Aleksey, Leigh, Nigel, Al-Chalabi, Ammar, Shaw, Christopher E, Traynor, Bryan J, Chiò, Adriano, Restagno, Gabriella, Mora, Gabriele, Ophoff, Roel A, Oksenberg, Jorge R, Van Damme, Philip, Compston, Alastair, Robberecht, Wim, Dubois, Bénédicte, van den Berg, Leonard H, De Jager, Philip L, Veldink, Jan H, and de Bakker, Paul IW

Subjects
Human Genome, ALS, Multiple Sclerosis, Rare Diseases, Autoimmune Disease, Neurosciences, Genetics, Neurodegenerative, Clinical Research, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Amyotrophic Lateral Sclerosis, Comorbidity, Genetic Predisposition to Disease, Humans, Polymorphism, Single Nucleotide, International Multiple Sclerosis Genetics Consortium, Australia and New Zealand MS Genetics Consortium, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Genome-wide association studies have been successful in identifying common variants that influence the susceptibility to complex diseases. From these studies, it has emerged that there is substantial overlap in susceptibility loci between diseases. In line with those findings, we hypothesized that shared genetic pathways may exist between multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While both diseases may have inflammatory and neurodegenerative features, epidemiological studies have indicated an increased co-occurrence within individuals and families. To this purpose, we combined genome-wide data from 4088 MS patients, 3762 ALS patients and 12 030 healthy control individuals in whom 5 440 446 single-nucleotide polymorphisms (SNPs) were successfully genotyped or imputed. We tested these SNPs for the excess association shared between MS and ALS and also explored whether polygenic models of SNPs below genome-wide significance could explain some of the observed trait variance between diseases. Genome-wide association meta-analysis of SNPs as well as polygenic analyses fails to provide evidence in favor of an overlap in genetic susceptibility between MS and ALS. Hence, our findings do not support a shared genetic background of common risk variants in MS and ALS.

Published
2014

3. Mapping of gene expression reveals CYP27A1 as a susceptibility gene for sporadic ALS.

Author

Diekstra, Frank P, Saris, Christiaan GJ, van Rheenen, Wouter, Franke, Lude, Jansen, Ritsert C, van Es, Michael A, van Vught, Paul WJ, Blauw, Hylke M, Groen, Ewout JN, Horvath, Steve, Estrada, Karol, Rivadeneira, Fernando, Hofman, Albert, Uitterlinden, Andre G, Robberecht, Wim, Andersen, Peter M, Melki, Judith, Meininger, Vincent, Hardiman, Orla, Landers, John E, Brown, Robert H, Shatunov, Aleksey, Shaw, Christopher E, Leigh, P Nigel, Al-Chalabi, Ammar, Ophoff, Roel A, van den Berg, Leonard H, and Veldink, Jan H

Subjects
Motor Neurons, Humans, Amyotrophic Lateral Sclerosis, Xanthomatosis, Cerebrotendinous, Genetic Predisposition to Disease, Gene Expression Profiling, Pedigree, Genotype, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study, HapMap Project, Cholestanetriol 26-Monooxygenase, Xanthomatosis, Cerebrotendinous, Polymorphism, Single Nucleotide, General Science & Technology
Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls) were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls). These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls). Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27 × 10(-51)) withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible susceptibility gene for ALS.

Published
2012

4. Gene-network analysis identifies susceptibility genes related to glycobiology in autism.

Author

van der Zwaag, Bert, Franke, Lude, Poot, Martin, Hochstenbach, Ron, Spierenburg, Henk A, Vorstman, Jacob AS, van Daalen, Emma, de Jonge, Maretha V, Verbeek, Nienke E, Brilstra, Eva H, van 't Slot, Ruben, Ophoff, Roel A, van Es, Michael A, Blauw, Hylke M, Veldink, Jan H, Buizer-Voskamp, Jacobine E, Beemer, Frits A, van den Berg, Leonard H, Wijmenga, Cisca, van Amstel, Hans Kristian Ploos, van Engeland, Herman, Burbach, J Peter H, and Staal, Wouter G

Subjects
Brain, Animals, Humans, Mice, Genetic Predisposition to Disease, Oligonucleotide Array Sequence Analysis, Case-Control Studies, Reproducibility of Results, Autistic Disorder, Chromosome Segregation, Gene Expression Regulation, Developmental, Gene Dosage, Haplotypes, Genome, Human, Software, Gene Regulatory Networks, Glycomics, Gene Expression Regulation, Developmental, Genome, Human, General Science & Technology
Abstract

The recent identification of copy-number variation in the human genome has opened up new avenues for the discovery of positional candidate genes underlying complex genetic disorders, especially in the field of psychiatric disease. One major challenge that remains is pinpointing the susceptibility genes in the multitude of disease-associated loci. This challenge may be tackled by reconstruction of functional gene-networks from the genes residing in these loci. We applied this approach to autism spectrum disorder (ASD), and identified the copy-number changes in the DNA of 105 ASD patients and 267 healthy individuals with Illumina Humanhap300 Beadchips. Subsequently, we used a human reconstructed gene-network, Prioritizer, to rank candidate genes in the segmental gains and losses in our autism cohort. This analysis highlighted several candidate genes already known to be mutated in cognitive and neuropsychiatric disorders, including RAI1, BRD1, and LARGE. In addition, the LARGE gene was part of a sub-network of seven genes functioning in glycobiology, present in seven copy-number changes specifically identified in autism patients with limited co-morbidity. Three of these seven copy-number changes were de novo in the patients. In autism patients with a complex phenotype and healthy controls no such sub-network was identified. An independent systematic analysis of 13 published autism susceptibility loci supports the involvement of genes related to glycobiology as we also identified the same or similar genes from those loci. Our findings suggest that the occurrence of genomic gains and losses of genes associated with glycobiology are important contributors to the development of ASD.

Published
2009

5. Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS

Author

Hop, Paul J., Zwamborn, Ramona A. J., Hannon, Eilis, Shireby, Gemma L., Nabais, Marta F., Walker, Emma M., van Rheenen, Wouter, van Vugt, Joke J. F. A., Dekker, Annelot M., Westeneng, Henk-Jan, Tazelaar, Gijs H. P., Slagboom, P. Eline, Beekman, Marian, Deelen, Joris, van Heemst, Diana, Veldink, Jan H., van den Berg, Leonard H., van Duijn, Cornelia M., Hofman, Bert A., Isaacs, Aaron, Uitterlinden, Andre G., van Eijk, Kristel R., van Meurs, Joyce, Jhamai, P. Mila, Verbiest, Michael, Suchiman, H. Eka D., Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Mei, Hailiang, van Iterson, Maarten, Moisse, Matthieu, van Galen, Michiel, Bot, Jan, Zhernakova, Dasha V., Jansen, Rick, van ‘t Hof, Peter, Deelen, Patrick, Nooren, Irene, t Hoen, Peter A. C., Heijmans, Bastiaan T., Moed, Matthijs, Baird, Denis, Franke, Lude, Vermaat, Martijn, Luijk, Rene, Jan Bonder, Marc, van Dijk, Freerk, Arindrarto, Wibowo, Al Khleifat, Ahmad, Kielbasa, Szymon M., Swertz, Morris A., van Zwet, Erik W., Al-Chalabi, Ammar, Wray, Naomi R., Bensimon, Gilbert, Hardiman, Orla, Iacoangeli, Alfredo, Chio, Adriano, Smith, George Davey, Mill, Jonathan, Ticozzi, Nicola, Ratti, Antonia, Cooper-Knock, Jonathan, Morrison, Karen E., Shaw, Pamela J., Basak, A. Nazli, Chiò, Adriano, Calvo, Andrea, Moglia, Cristina, Canosa, Antonio, Brunetti, Maura, Grassano, Maurizio, Gotkine, Marc, Lerner, Yossef, Zabari, Michal, Vourc’h, Patrick, Corcia, Philippe, Couratier, Philippe, Mora Pardina, Jesus S., Salas, Teresa, Dion, Patrick, Ross, Jay P., Henderson, Robert D., Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Nicholson, Garth, Rowe, Dominic B., Pamphlett, Roger, Mather, Karen A., Sachdev, Perminder S., Furlong, Sarah, Garton, Fleur C., Henders, Anjali K., Lin, Tian, Ngo, Shyuan T., Steyn, Frederik J., Wallace, Leanne, Williams, Kelly L., Neto, Miguel Mitne, Cauchi, Ruben J., Blair, Ian P., Kiernan, Matthew C., Drory, Vivian, Povedano, Monica, Carvalho, Mamede, Pinto, Susana, Weber, Markus, Rouleau, Guy A., Silani, Vincenzo, Landers, John E., Shaw, Christopher E., Andersen, Peter M., McRae, Allan F., van Es, Michael A., Pasterkamp, R. Jeroen, McLaughlin, Russell L., Kenna, Kevin P., Tsai, Ellen, Runz, Heiko, Van Damme, Philip, Boomsma, Dorret I., Pool, Rene, van Dongen, Jenny, Hottenga, Joukje J., van Greevenbroek, Marleen M. J., Stehouwer, Coen D.A., van der Kallen, Carla J.H., Schalkwijk, Casper G., Wijmenga, Cisca, Zhernakova, Sasha, Tigchelaar, Ettje F., Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Laboratory Medicine, APH - Mental Health, Internal Medicine, Epidemiology, and Repositório da Universidade de Lisboa

Subjects
Cholesterol, Amyotrophic Lateral Sclerosis, Humans, Neurodegenerative Diseases, General Medicine, DNA Methylation, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Article, Epigenesis, Genetic, Genome-Wide Association Study
Abstract

Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works., Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions., The research reported in this publication was supported by grants from The Dutch Research Council (NWO) (VENI scheme grant 09150161810018 to W.v.R.) and Prinses Beatrix Spierfond (neuromuscular fellowship grant W.F19-03 to W.v.R.), The Prinses Beatrix Spierfonds (W.OR20-08 to J.J.F.A.v.V. and J.H.V.), The Canadian Institutes of Health Research (FRN 159279 to J.P.R.), The Dutch Research Council (NWO) (VIDI grant 91719350 to K.P.K.), The European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 772376-EScORIAL to J.H.V.), the Swedish Brain Foundation (grant nos. 2012-0262, 2012-0305, 2013-0279, 2016-0303, 2018-0310, and 2020-0353 to P.M.A.), the Swedish Research Council (grant nos. 2012-3167 and 2017-03100 to P.M.A.), the Knut and Alice Wallenberg Foundation (grant nos. 2012.0091, 2014.0305, and 2020.0232 to P.M.A.), the Ulla-Carin Lindquist Foundation and the Västerbotten County Council (grant no. 56103-7002829 to P.M.A.), and King Gustaf V’s and Queen Victoria’s Freemason’s Foundation. This is an EU Joint Programme–Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND (www.jpnd.eu) [United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)] and through the Motor Neurone Disease Association (MNDA). This study represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. A.A.-C. is supported by an NIHR Senior Investigator Award. Samples used in this research were entirely/in part obtained from the U.K. National DNA Bank for MND Research, funded by the MND Association and the Wellcome Trust. We would like to thank people with MND and their families for their participation in this project. We acknowledge sample management undertaken by Biobanking Solutions funded by the Medical Research Council at the Centre for Integrated Genomic Medical Research, University of Manchester. R.J.P. is funded through the Gravitation program of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (BRAINSCAPES). G.L.S. was supported by a PhD studentship from the Alzheimer’s Society. S.T.N. acknowledges support through a FightMND Mid-Career Fellowship. V.S. is supported by the Italian Ministry of Health, AriSLA, and E-Rare Joint Transnational Call. A.A.K. is funded by the MNDA and NIHR Maudsley Biomedical Research Centre. D.B., E.T., and H.R. are employees of Biogen. L.H.v.d.B. reports grants from the Netherlands ALS Foundation, grants from The Netherlands Organization for Health Research and Development (Vici scheme), grants from The European Community’s Health Seventh Framework Programme [grant agreement no. 259867 (EuroMOTOR) to L.H.v.d.B.], and grants from The Netherlands Organization for Health Research and Development (the STRENGTH project, funded through the EU Joint Programme–Neurodegenerative Disease Research, JPND), during the conduct of the study. Project MinE Belgium was supported by a grant from IWT (no. 140935), the ALS Liga België, the National Lottery of Belgium, and the KU Leuven Opening the Future Fund. P.V.D. holds a senior clinical investigatorship of FWO-Vlaanderen and is supported by the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga België, and the KU Leuven funds “Een Hart voor ALS”, “Laeversfonds voor ALS Onderzoek”, and the “Valéry Perrier Race against ALS Fund”. This work was supported by the Italian Ministry of Health (Ministero della Salute, Ricerca Sanitaria Finalizzata, grant RF-2016-02362405 to A. Chiò), the Progetti di Rilevante Interesse Nazionale program of the Ministry of Education, University and Research (grant 2017SNW5MB to A. Chiò); the European Commission’s Health Seventh Framework Programme (FP7/2007-2013 under grant agreement 259867 to A. Chiò), and the Joint Programme–Neurodegenerative Disease Research (Strength, ALS-Care and Brain-Mend projects), granted by Italian Ministry of Education, University, and Research. This study was performed under the Department of Excellence grant of the Italian Ministry of Education, University and Research to the “Rita Levi Montalcini” Department of Neuroscience, University of Torino, Italy. We acknowledge funding from the Australian National Health and Medical Research (NHMRC) Council: 1151854, 1083187, 1173790, 1078901, 1113400, 1095215, and 1176913 Enabling Grant #402703 to N.R.W. Additional funding was provided by the Motor Neurone Disease Research Institute of Australia Ice Bucket Challenge grant for the SALSA-SGC consortium. The OATS (used for controls) was facilitated through Twins Research Australia, a national resource in part supported by a Centre for Research Excellence from the Australian NHMRC Council (NHMRC 1079102 to N.R.W.). Funding for this study was awarded by the (NHMRC)/Australian Research Council Strategic Award (grant 401162 to N.R.W.) and NHMRC grants (1405325, 1024224, 1025243, 1045325, 1085606, 568969, and 1093083 to N.R.W.). The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. This study was supported by the ALS Foundation Netherlands. This work was sponsored by NWO Domain Science for the use of the national computer facilities. A.N.B. is grateful to the Suna and Inan Kirac Foundation and Koc University for the excellent research environment created and for financial support. G.A.R. is supported by the Canadian Institutes of Health. Several authors of this publication are members of the Netherlands Neuromuscular Center (NL-NMD) and the European Reference Network for rare neuromuscular diseases EURO-NMD. French ALS patients of the Pitié-Salpêtrière hospital (Paris) have been collected with ARSla funding support.

Published
2022

6. A case of ALS with posterior cortical atrophy

Author

Nijboer, Tanja C.W., Nitert, Bram, Westeneng, Henk Jan, Van Den Berg, Leonard H., van Es, Michael A., Experimental Psychology (onderzoeksprogramma PF), Leerstoel Postma, Helmholtz Institute, Experimental Psychology (onderzoeksprogramma PF), Leerstoel Postma, and Helmholtz Institute

Subjects
Pathology, medicine.medical_specialty, Neurology, MND-FTD continuum, Clinical Neurology, posterior cortical atrophy, Disease, Asymptomatic, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Humans, Medicine, Amyotrophic lateral sclerosis, Aged, business.industry, Brain, Posterior cortical atrophy, medicine.disease, Magnetic Resonance Imaging, Clinical neurology, Frontotemporal Dementia, Disease Progression, Female, Neurology (clinical), medicine.symptom, Cognition Disorders, business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Here, we provide a case-report of an amyotrophic lateral sclerosis (ALS) patient with cognitive deficits best defined as posterior cortical atrophy (PCA). This is an unusual finding as ALS forms a spectrum with frontotemporal dementia (FTD), whereas PCA is predominantly associated with Alzheimer’s disease pathology. We hypothesize on whether ALS with PCA might be an under recognized phenotype considering multiple imaging studies in ALS have also reported (asymptomatic) parietal atrophy.

Published
2019

7. Is it accurate to classify ALS as a neuromuscular disorder?

Author

van Es, Michael A, Goedee, H Stephan, Westeneng, Henk-Jan, Nijboer, Tanja C W, van den Berg, Leonard H, Helmholtz Institute, Experimental Psychology (onderzoeksprogramma PF), Leerstoel Postma, Afd Psychologische functieleer, Helmholtz Institute, Experimental Psychology (onderzoeksprogramma PF), Leerstoel Postma, and Afd Psychologische functieleer

Subjects
business.industry, TDP-43, General Neuroscience, Amyotrophic lateral sclerosis(ALS), Neurodegeneration, Amyotrophic Lateral Sclerosis, neurodegeneration, Neurodegenerative Diseases, Neuromuscular Diseases, medicine.disease, frontotemporaldementia (FTD), 030227 psychiatry, Domain (software engineering), 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Pharmacology (medical), Neurology (clinical), Amyotrophic lateral sclerosis, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by the progressive loss of upper and lower motor neurons. ALS has traditionally been classified within the domain of neuromuscular diseases, which are a unique spectrum of disorders that predominantly affect the peripheral nervous system. However, over the past decades compounding evidence has emerged that there is extensive involvement of the central nervous system. Therefore, one can question whether it remains accurate to classify ALS as a neuromuscular disorder. AREAS COVERED: In this review, the authors sought to discuss current approaches toward disease classification and how we should classify ALS based on novel insights from clinical, imaging, pathophysiological, neuropathological and genetic studies. EXPERT OPINION: ALS exhibits the cardinal features of a neurodegenerative disease. Therefore, classifying ALS as a neuromuscular disease in the strict sense has become untenable. Diagnosing ALS however does require significant neuromuscular expertise and therefore neuromuscular specialists remain best equipped to evaluate this category of patients. Designating motor neuron diseases as a separate category in the ICD-11 is justified and adequately deals with this issue. However, to drive effective therapy development the fields of motor neuron disease and neurodegenerative disorders must come together.

Published
2020

8. Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Author

Schijven, D., Stevelink, R., Mccormack, M., van Rheenen, W., Luykx, J. J., Koeleman, B. P. C., Veldink, J. H., Aleksey, Shatunov, Mclaughlin, Russell L., van der Spek, Rick A. A., Alfredo, Iacoangeli, Kenna, Kevin P., van Eijk, Kristel R., Nicola, Ticozzi, Boris, Rogelj, Katarina, Vrabec, Metka, Ravnik-Glavač, Blaž, Koritnik, Janez, Zidar, Lea, Leonardis, Leja Dolenc Grošelj, Stéphanie, Millecamps, François, Salachas, Vincent, Meininger, Mamede de Carvalho, Susana, Pinto, Marta, Gromicho, Ana, Pronto-Laborinho, Mora, Jesus S., Ricardo, Rojas-García, Meraida, Polak, Siddharthan, Chandran, Shuna, Colville, Robert, Swingler, Morrison, Karen E., Shaw, Pamela J., John, Hardy, Orrell, Richard W., Alan, Pittman, Katie, Sidle, Pietro, Fratta, Andrea, Malaspina, Simon, Topp, Susanne, Petri, Susanna, Abdulla, Carsten, Drepper, Michael, Sendtner, Thomas, Meyer, Ophoff, Roel A., Staats, Kim A., Martina, Wiedau-Pazos, Catherine, Lomen-Hoerth, Van Deerlin, Vivianna M., Trojanowski, John Q., Lauren, Elman, Leo, Mccluskey, Nazli Basak, A., Thomas, Meitinger, Peter, Lichtner, Milena, Blagojevic-Radivojkov, Andres, Christian R., Gilbert, Bensimon, Bernhard, Landwehrmeyer, Alexis, Brice, Payan, Christine A. M., Safaa, Saker-Delye, Alexandra, Dürr, Wood, Nicholas W., Lukas, Tittmann, Wolfgang, Lieb, Andre, Franke, Marcella, Rietschel, Sven, Cichon, Nöthen, Markus M., Philippe, Amouyel, Christophe, Tzourio, Jean-François, Dartigues, Uitterlinden, Andre G., Fernando, Rivadeneira, Karol, Estrada, Albert, Hofman, Charles, Curtis, van der Kooi, Anneke J., Markus, Weber, Shaw, Christopher E., Smith, Bradley N., Daisy, Sproviero, Cristina, Cereda, Mauro, Ceroni, Luca, Diamanti, Roberto Del Bo, Stefania, Corti, Comi, Giacomo P., Sandra, D'Alfonso, Lucia, Corrado, Bertolin, Cinzia, Soraru', Gianni, Letizia, Mazzini, Viviana, Pensato, Cinzia, Gellera, Cinzia, Tiloca, Antonia, Ratti, Andrea, Calvo, Cristina, Moglia, Maura, Brunetti, Simona, Arcuti, Rosa, Capozzo, Chiara, Zecca, Christian, Lunetta, Silvana, Penco, Nilo, Riva, Alessandro, Padovani, Massimiliano, Filosto, Ian, Blair, Nicholson, Garth A., Rowe, Dominic B., Roger, Pamphlett, Kiernan, Matthew C., Julian, Grosskreutz, Witte, Otto W., Robert, Steinbach, Tino, Prell, Beatrice, Stubendorff, Ingo, Kurth, Hübner, Christian A., Nigel Leigh, P., Federico, Casale, Adriano, Chio, Ettore, Beghi, Elisabetta, Pupillo, Rosanna, Tortelli, Giancarlo, Logroscino, John, Powell, Ludolph, Albert C., Weishaupt, Jochen H., Wim, Robberecht, Philip Van Damme, Brown, Robert H., Glass, Jonathan D., Landers, John E., Orla, Hardiman, Andersen, Peter M., Philippe, Corcia, Patrick, Vourc'H, Vincenzo, Silani, van Es, Michael A., Jeroen Pasterkamp, R., Lewis, Cathryn M., Gerome, Breen, Ammar, Al-Chalabi, van den Berg, Leonard H., Veldink, Jan H., Daniela, Calini, Isabella, Fogh, Barbara, Castellotti, Franco, Taroni, Stella, Gagliardi, Giacomo, Comi, Sandra, D’Alfonso, Pegoraro, Elena, Giorgia, Querin, Francesca, Gerardi, Fabrizio, Rinaldi, Maria Sofia Cotelli, Luca, Chiveri, Maria Cristina Guaita, Patrizia, Perrone, Giancarlo, Comi, Carlo, Ferrarese, Lucio, Tremolizzo, Marialuisa, Delodovici, Giorgio, Bono, Stefania, Cammarosano, Antonio, Canosa, Dario, Cocito, Leonardo, Lopiano, Luca, Durelli, Bruno, Ferrero, Antonio, Bertolotto, Alessandro, Mauro, Luca, Pradotto, Roberto, Cantello, Enrica, Bersano, Dario, Giobbe, Maurizio, Gionco, Daniela, Leotta, Lucia, Appendino, Cavallo, Cavallo, Enrico, Odddenino, Claudio, Geda, Fabio, Poglio, Paola, Santimaria, Umberto, Massazza, Antonio, Villani, Roberto, Conti, Fabrizio, Pisano, Mario, Palermo, Franco, Vergnano, Paolo, Provera, Maria Teresa Penza, Marco, Aguggia, Nicoletta Di Vito, Piero, Meineri, Ilaria, Pastore, Paolo, Ghiglione, Danilo, Seliak, Nicola, Launaro, Giovanni, Astegiano, Bottacchi, Edo, Isabella Laura Simone, Stefano, Zoccolella, Michele, Zarrelli, Franco, Apollo, William, Camu, Jean Sebastien Hulot, Francois, Viallet, Philippe, Couratier, David, Maltete, Christine, Tranchant, Marie, Vidailhet, Bassel, Abou-Khalil, Pauls, Auce, Andreja, Avbersek, Melanie, Bahlo, David, J Balding, Thomas, Bast, Larry, Baum, Albert, J Becker, Felicitas, Becker, Bianca, Berghuis, Samuel, F Berkovic, Katja, E Boysen, Jonathan, P Bradfield, Lawrence, C Brody, Russell, J Buono, Ellen, Campbell, Gregory, D Cascino, Claudia, B Catarino, Gianpiero, L Cavalleri, Stacey, S Cherny, Krishna, Chinthapalli, Alison, J Coffey, Alastair, Compston, Antonietta, Coppola, Patrick, Cossette, John, J Craig, Gerrit-Jan de Haan, Peter De Jonghe, Carolien G, F de Kovel, Norman, Delanty, Chantal, Depondt, Orrin, Devinsky, Dennis, J Dlugos, Colin, P Doherty, Christian, E Elger, Johan, G Eriksson, Thomas, N Ferraro, Martha, Feucht, Ben, Francis, Jacqueline, A French, Saskia, Freytag, Verena, Gaus, Eric, B Geller, Christian, Gieger, Tracy, Glauser, Simon, Glynn, David, B Goldstein, Hongsheng, Gui, Youling, Guo, Kevin, F Haas, Hakon, Hakonarson, Kerstin, Hallmann, Sheryl, Haut, Erin, L Heinzen, Ingo, Helbig, Christian, Hengsbach, Helle, Hjalgrim, Michele, Iacomino, Andrés, Ingason, Michael, R Johnson, Reetta, Kälviäinen, Anne-Mari, Kantanen, Dalia, Kasperavičiūte, Dorothee Kasteleijn-Nolst Trenite, Heidi, E Kirsch, Robert, C Knowlton, Bobby P, C Koeleman, Roland, Krause, Martin, Krenn, Wolfram, S Kunz, Ruben, Kuzniecky, Patrick, Kwan, Dennis, Lal, Yu-Lung, Lau, Anna-Elina, Lehesjoki, Holger, Lerche, Costin, Leu, Dick, Lindhout, Warren, D Lo, Iscia, Lopes-Cendes, Daniel, H Lowenstein, Alberto, Malovini, Anthony, G Marson, Thomas, Mayer, Mark, Mccormack, James, L Mills, Nasir, Mirza, Martina, Moerzinger, Rikke, S Møller, Anne, M Molloy, Hiltrud, Muhle, Mark, Newton, Ping-Wing, Ng, Markus, M Nöthen, Peter, Nürnberg, Terence, J O’Brien, Karen, L Oliver, Aarno, Palotie, Faith, Pangilinan, Sarah, Peter, Slavé, Petrovski, Annapurna, Poduri, Michael, Privitera, Rodney, Radtke, Sarah, Rau, Philipp, S Reif, Eva, M Reinthaler, Felix, Rosenow, Josemir, W Sander, Thomas, Sander, Theresa, Scattergood, Steven, C Schachter, Christoph, J Schankin, Ingrid, E Scheffer, Bettina, Schmitz, Susanne, Schoch, Pak, C Sham, Jerry, J Shih, Graeme, J Sills, Sanjay, M Sisodiya, Lisa, Slattery, Alexander, Smith, David, F Smith, Michael, C Smith, Philip, E Smith, Anja C, M Sonsma, Doug, Speed, Michael, R Sperling, Bernhard, J Steinhoff, Ulrich, Stephani, Remi, Stevelink, Konstantin, Strauch, Pasquale, Striano, Hans, Stroink, Rainer, Surges, K Meng Tan, Liu Lin Thio, G Neil Thomas, Marian, Todaro, Rossana, Tozzi, Maria, S Vari, Eileen P, G Vining, Frank, Visscher, Sarah von Spiczak, Nicole, M Walley, Yvonne, G Weber, Zhi, Wei, Judith, Weisenberg, Christopher, D Whelan, Peter, Widdess-Walsh, Markus, Wolff, Stefan, Wolking, Wanling, Yang, Federico, Zara, Fritz, Zimprich, Project MinE ALS GWAS Consortium, International League Against Epilepsy Consortium on Complex Epilepsies, Department of Medical and Clinical Genetics, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, and HUS Helsinki and Uusimaa Hospital District

Subjects
Risk, 0301 basic medicine, Aging, Genetic correlation, Geriatrics & Gerontology, education, Genome-wide association study, Biology, ALS, Epilepsy, Amyotrophic Lateral Sclerosis, Gene Frequency, Humans, Genetic Variation, Genome-Wide Association Study, Negative Results, Article, 3124 Neurology and psychiatry, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, medicine, Amyotrophic lateral sclerosis, Allele frequency, Genetics, Science & Technology, Mechanism (biology), General Neuroscience, 3112 Neurosciences, Neurosciences, medicine.disease, 3. Good health, Minor allele frequency, 030104 developmental biology, Neurology (clinical), Neurosciences & Neurology, Geriatrics and Gerontology, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins. ispartof: NEUROBIOLOGY OF AGING vol:92 ispartof: location:United States status: published

Published
2020

9. Epidemiology of paediatric moderate and severe traumatic brain injury in the Netherlands

Author

Jochems, Denise, van Rein, Eveline, Niemeijer, Menco, van Heijl, M., van Es, Michael A., Nijboer, Tanja, Leenen, L.P.H., Houwert, R.M., van Wessem, Karlijn J.P., Leerstoel Postma, Helmholtz Institute, and Experimental Psychology (onderzoeksprogramma PF)

Subjects
medicine.medical_specialty, Pediatrics, Adolescent, Traumatic brain injury, Epidemiology, Brain Injuries, Traumatic, medicine, Humans, Child, Netherlands, Retrospective Studies, Cause of death, business.industry, Glasgow Outcome Scale, Incidence (epidemiology), Mortality rate, Incidence, Retrospective cohort study, General Medicine, medicine.disease, Hospitalization, Paediatric, Child, Preschool, Mechanism of injury, Pediatrics, Perinatology and Child Health, Neurology (clinical), business
Abstract

Introduction Traumatic brain injury (TBI) is the main cause of death in children around the world. The last Dutch epidemiological study described the incidence over 10 years ago. Mechanism of injury seems to change with the age of the child, therefore it is important to appreciate different age groups. To be able to lower the impact of childhood TBI, an understanding of current incidence, mechanism of injury and outcome is necessary. Methods A nationwide retrospective cohort study was conducted. The Dutch National Trauma Database was used to identify all patients 18 years and younger who were admitted to a Dutch hospital with moderate-severe TBI (Abbreviated Injury Score≥3) in the Netherlands, from January 2015 until December 2017. Subanalyses were done for different age groups. Results In total, 1413 patients were included, of whom 5% died. The incidence rate of moderate-severe TBI was 14/100,000 person years. Median age was 10.4 years. Largest age group was patients

Published
2021

10. Incidence, causes and consequences of moderate and severe traumatic brain injury as determined by Abbreviated Injury Score in the Netherlands

Author

Jochems, Denise, van Rein, Eveline, Niemeijer, Menco, van Heijl, Mark, van Es, Michael A., Nijboer, Tanja, Leenen, Luke P, Houwert, R. Marijn, van Wessem, Karlijn J.P., Leerstoel Postma, Helmholtz Institute, Experimental Psychology (onderzoeksprogramma PF), Leerstoel Postma, Helmholtz Institute, and Experimental Psychology (onderzoeksprogramma PF)

Subjects
Male, medicine.medical_specialty, Traumatic brain injury, Science, Trauma, Article, Cohort Studies, Very frequent, Injury Severity Score, Brain Injuries, Traumatic, Epidemiology, medicine, Humans, Aged, Netherlands, Retrospective Studies, Cause of death, Aged, 80 and over, Multidisciplinary, Multiple Trauma, business.industry, Incidence, Mortality rate, Incidence (epidemiology), Accidents, Traffic, Retrospective cohort study, Middle Aged, medicine.disease, Polytrauma, Hospitalization, Neurology, Emergency medicine, Medicine, Accidental Falls, Female, business
Abstract

Traumatic brain injury (TBI) is a leading cause of death and disability. Epidemiology seems to be changing. TBIs are increasingly caused by falls amongst elderly, whilst we see less polytrauma due to road traffic accidents (RTA). Data on epidemiology is essential to target prevention strategies. A nationwide retrospective cohort study was conducted. The Dutch National Trauma Database was used to identify all patients over 17 years old who were admitted to a hospital with moderate and severe TBI (AIS ≥ 3) in the Netherlands from January 2015 until December 2017. Subgroup analyses were done for the elderly and polytrauma patients. 12,295 patients were included in this study. The incidence of moderate and severe TBI was 30/100.000 person-years, 13% of whom died. Median age was 65 years and falls were the most common trauma mechanism, followed by RTAs. Amongst elderly, RTAs consisted mostly of bicycle accidents. Mortality rates were higher for elderly (18%) and polytrauma patients (24%). In this national database more elderly patients who most often sustained the injury due to a fall or an RTA were seen. Bicycle accidents were very frequent, suggesting prevention could be an important aspect in order to decrease morbidity and mortality.

Published
2021

11. A neuropsychological and behavioral study of PLS

Author

de Vries, Bálint S., Spreij, Lauriane A., Rustemeijer, Laura M.M., Bakker, Leonhard A., Veldink, Jan H., van den Berg, Leonard H., Nijboer, Tanja C.W., van Es, Michael, Leerstoel Postma, Experimental Psychology (onderzoeksprogramma PF), Helmholtz Institute, Afd Psychologische functieleer, Leerstoel Postma, Experimental Psychology (onderzoeksprogramma PF), Helmholtz Institute, and Afd Psychologische functieleer

Subjects
Male, cognition, medicine.medical_specialty, Neurology, Theory of Mind, Clinical Neurology, Audiology, Neuropsychological Tests, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Social cognition, Primary lateral sclerosis, Theory of mind, medicine, Journal Article, Humans, Amyotrophic lateral sclerosis, Motor Neuron Disease, Social Behavior, neuropsychological evaluation, Aged, Aged, 80 and over, Neuropsychology, Cognition, FTD, Middle Aged, Executive functions, medicine.disease, Female, Neurology (clinical), Psychology, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Background: Primary lateral sclerosis (PLS) is a rare motor neuron disease characterized by progressive degeneration of upper motor neurons, resulting in spasticity and disability. There is, however, mounting evidence that the disease is not limited to upper motor neurons alone and that cognitive and behavioral changes within the spectrum of frontotemporal dementia (FTD) are part of the clinical phenotype. Objectives: To provide an in-depth classification of the cognitive and behavioral profiles of PLS by using the golden standard, a full neuropsychological evaluation, as well as a comprehensive behavioral assessment in a cohort of 30 cases. Results: Only 7 out of 30 PLS patients scored within normal range on all of the tests within our battery. The neuropsychological profile of PLS consists of deficits in social cognition (affective theory of mind (ToM) in particular), fluency, executive functions and memory. Using the revised Strong criteria, we could classify 57% of patients within the FTD spectrum (of which 17% had behavioral variant FTD). An additional 20% of patients had deficits which were not characteristic of FTD. Conclusions: This study confirms that PLS is not a restricted phenotype (only affecting upper motor neurons) and that behavioral and cognitive changes are common. Therefore, clinicians treating PLS patients should routinely assess cognition and behavior as part of routine care as cognitive and behavioral changes impact management, decision-making and care-giver burden. This assessment should be sensitive to the neuropsychological profile of PLS (social cognition (affective ToM in particular), fluency, executive functions and memory) and behavioral changes.

Published
2019

12. Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort

Author

Tazelaar, Gij SHP, Dekker, Annelot M, van Vugt, Joke JFA, van der Spek, Rick A, Westeneng, Henk-Jan, Kool, Lindy JBG, Kenna, Kevin P, van Rheenen, Wouter, Pulit, Sara L, McLaughlin, Russell L, Sproviero, William, Iacoangeli, Alfredo, Huebers, Annemarie, Brenner, David, Morrison, Karen E, Shaw, Pamela J, Shaw, Christopher E, Povedano Panades, Monica, Mora Pardina, Jesus S, Glass, Jonathan D, Hardiman, Orla, Al-Chalabi, Ammar, van Damme, Philip, Robberecht, Wim, Landers, John E, Ludolph, Albert C, Weishaupt, Jochen H, van den Berg, Leonard H, Veldink, Jan H, van Es, Michael A, Akcimen, Fulya, Al Khleifat, Ahmad, Andersen, Peter, Basak, A Nazli, Bauer, Denis C, Blair, Ian, Brands, William J, Byrne, Ross P, Calvo, Andrea, Gonzalez, Yolanda Campos, Chio, Adriano, Cooper-Knock, Jonothan, Corcia, Philippe, Couratier, Philippe, de Carvalho, Mamede, Drory, Vivian E, Eitan, Chen, Garcia Redondo, Alberto, Gellera, Cinzia, Gotkine, Marc, Hornstein, Eran, Kenna, Brendan, Kiernan, Matthew C, Kocoglu, Cemile, Kooyman, Maarten, Lopez Alonso, Victoria, Middelkoop, Bas, Mill, Jonathan, Mitne-Neto, Miguel, Moisse, Matthieu, Pinto, Susana C, Ratti, Antonia, Schellevis, Raymond D, Shatunov, Aleksey, Silani, Vincenzo, Staiger, Christine, Tazelaar, Gijs HP, Ticozzi, Nicola, Tunca, Ceren, Twine, Nathalie A, van Doormaal, Perry TC, van Eijk, Kristel R, Visscher, Peter M, Vourch, Patrick, Weber, Markus, Williams, Kelly L, Wray, Naomi, Yang, Jian, Zatz, Mayana, and Zhang, Katharine

Subjects
0301 basic medicine, Oncology, Male, Aging, Geriatrics & Gerontology, Internationality, Cohort Studies, 0302 clinical medicine, Copy-number variation, Amyotrophic lateral sclerosis, Non-U.S. Gov't, DNA Repeat Expansion, General Neuroscience, Research Support, Non-U.S. Gov't, Amyotrophic Lateral Sclerosis/genetics, GENOME, Cohort, Female, Life Sciences & Biomedicine, Cohort study, medicine.medical_specialty, Hereditary spastic paraplegia, Neuroscience(all), NIPA1, Clinical Neurology, HEREDITARY SPASTIC PARAPLEGIA, Research Support, Article, 03 medical and health sciences, DNA Repeat Expansion/genetics, Meta-Analysis as Topic, Internal medicine, Angelman syndrome, medicine, Journal Article, Humans, Membrane Proteins/genetics, Genetic Association Studies, Science & Technology, business.industry, Neurosciences, Membrane Proteins, Repeat expansion, medicine.disease, Ageing, 030104 developmental biology, Logistic Models, Neurosciences & Neurology, Neurology (clinical), Geriatrics and Gerontology, Peptides, business, Trinucleotide repeat expansion, Peptides/genetics, 030217 neurology & neurosurgery, Developmental Biology
Abstract

NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome 1) mutations are known to cause hereditary spastic paraplegia type 6, a neurodegenerative disease that phenotypically overlaps to some extent with amyotrophic lateral sclerosis (ALS). Previously, a genomewide screen for copy number variants found an association with rare deletions in NIPA1 and ALS, and subsequent genetic analyses revealed that long (or expanded) polyalanine repeats in NIPA1 convey increased ALS susceptibility. We set out to perform a large-scale replication study to further investigate the role of NIPA1 polyalanine expansions with ALS, in which we characterized NIPA1 repeat size in an independent international cohort of 3955 patients with ALS and 2276 unaffected controls and combined our results with previous reports. Meta-analysis on a total of 6245 patients with ALS and 5051 controls showed an overall increased risk of ALS in those with expanded (>8) GCG repeat length (odds ratio = 1.50, p = 3.8×10-5). Together with previous reports, these findings provide evidence for an association of an expanded polyalanine repeat in NIPA1 and ALS. ispartof: NEUROBIOLOGY OF AGING vol:74 ispartof: location:United States status: published

Published
2019

13. Cognitive and behavioural changes in PLS and PMA:challenging the concept of restricted phenotypes

Author

De Vries, Bálint S., Rustemeijer, Laura M.M., Bakker, Leonhard A., Schröder, Carin D., Veldink, Jan H., Van Den Berg, Leonard H., Nijboer, Tanja C.W., Van Es, Michael, Leerstoel Postma, Helmholtz Institute, Experimental Psychology (onderzoeksprogramma PF), Afd Psychologische functieleer, Leerstoel Postma, Helmholtz Institute, Experimental Psychology (onderzoeksprogramma PF), and Afd Psychologische functieleer

Subjects
Male, Adult, medicine.medical_specialty, Cognitive Dysfunction/diagnosis, Clinical Neurology, Neuropsychological Tests, Research Support, Muscular Atrophy, Spinal, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, 80 and over, medicine, Journal Article, Dementia, Humans, Cognitive Dysfunction, Muscular Atrophy, Spinal/psychology, Amyotrophic lateral sclerosis, Motor Neuron Disease, Non-U.S. Gov't, Primary Lateral Sclerosis, Aged, Retrospective Studies, Aged, 80 and over, business.industry, Mental Disorders, Research Support, Non-U.S. Gov't, Amyotrophic Lateral Sclerosis, Cognition, Retrospective cohort study, Motor Neuron Disease/psychology, Progressive muscular atrophy, Middle Aged, medicine.disease, Muscular Atrophy, Psychiatry and Mental health, Spinal/psychology, Phenotype, Amyotrophic Lateral Sclerosis/diagnosis, Anxiety, Female, Surgery, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Mental Disorders/epidemiology, Frontotemporal dementia
Abstract

ObjectivesCognitive and behavioural changes within the spectrum of frontotemporal dementia (FTD) are observed frequently in patients with amyotrophic lateral sclerosis (ALS). Whether these changes also occur in other forms of motor neuron disease (MND) is not well studied. We therefore systemically screened a large cohort of patients with primary lateral sclerosis (PLS) and progressive muscular atrophy (PMA) for cognitive and behavioural changes, and subsequently compared our findings with a cohort of patients with ALS.MethodsUsing a set of screening instruments (Edinburgh Cognitive and Behavioural ALS Screen, ALS and Frontotemporal Dementia Questionnaire, Frontal Assessment Battery, and Hospital Anxiety and Depression Scale), the presence of cognitive and behavioural changes as well as anxiety and depression in 277 patients with ALS, 75 patients with PLS and 143 patients with PMA was evaluated retrospectively.ResultsWe found a high frequency of cognitive and behavioural abnormalities with similar profiles in all three groups. Subjects with behavioural variant FTD were identified in all groups.ConclusionsThe percentage of patients with PLS and PMA with cognitive dysfunction was similar to patients with ALS, emphasising the importance for cognitive screening as part of routine clinical care in all three patient groups. With a similar cognitive profile, in line with genetic and clinical overlap between the MNDs, the view of PLS as an MND exclusively affecting upper motor neurons and PMA exclusively affecting lower motor neurons cannot be held. Therefore, our findings are in contrast to the recently revised El Escorial criteria of 2015, where PLS and PMA are described as restricted phenotypes. Our study favours a view of PLS and PMA as multidomain diseases similar to ALS.

Published
2019

14. Derivation of norms for the Dutch version of the Edinburgh cognitive and behavioral ALS screen

Author

Bakker, Leonhard A., Schröder, Carin D., Spreij, Lauriane A., Verhaegen, Marianne, De Vocht, Joke, Van Damme, Philip, Veldink, Jan H., Visser-Meily, Johanna M.A., van den Berg, Leonard H., Nijboer, Tanja C.W., van Es, Michael A., Leerstoel Postma, Helmholtz Institute, Experimental Psychology (onderzoeksprogramma PF), Afd Psychologische functieleer, Leerstoel Postma, Helmholtz Institute, Experimental Psychology (onderzoeksprogramma PF), and Afd Psychologische functieleer

Subjects
Male, Neurology, Neuropsychological Tests, Executive Function, 0302 clinical medicine, Reference Values, Amyotrophic lateral sclerosis, Non-U.S. Gov't, Language, Netherlands, SCORES, Research Support, Non-U.S. Gov't, Cognition, ECAS, IMPAIRMENT, Middle Aged, normative data, Female, Psychology, Life Sciences & Biomedicine, Clinical psychology, medicine.medical_specialty, Clinical Neurology, Research Support, DIAGNOSIS, VALIDATION, 03 medical and health sciences, AGE, Memory, cognitive dysfunction, LATERAL-SCLEROSIS SCREEN, medicine, Journal Article, Humans, In patient, Translations, Aged, Science & Technology, medicine.disease, DYSFUNCTION, Clinical neurology, VERBAL FLUENCY, Case-Control Studies, Normative, Edinburgh cognitive and behavioral ALS screen, Neurosciences & Neurology, sense organs, Neurology (clinical), 030217 neurology & neurosurgery
Abstract

BACKGROUND: The Edinburgh cognitive and behavioral ALS screen (ECAS) was developed specifically to detect cognitive and behavioral changes in patients with amyotrophic lateral sclerosis (ALS). Differences with regard to normative data of different (language) versions of neuropsychological tests such as the ECAS exist. OBJECTIVE: To derive norms for the Dutch version of the ECAS. METHODS: Normative data were derived from a large sample of 690 control subjects and cognitive profiles were compared between a matched sample of 428 patients with ALS and 428 control subjects. RESULTS: Age, level of education, and sex were significantly associated with performance on the ECAS in the normative sample. ECAS data were not normally distributed and therefore normative data were expressed as percentile ranks. The comparison of ECAS scores between patients and control subjects demonstrated that patients obtained significantly lower scores for language, executive function, verbal fluency, and memory, which is in line with the established cognitive profile of ALS. CONCLUSION: For an accurate interpretation of ECAS results, it is important to derive normative data in large samples with nonparametric methods. The present normative data provide healthcare professionals with an accurate estimate of how common or uncommon patients' ECAS scores are and provide a useful supplement to existing cut-off scores. ispartof: AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION vol:20 issue:1-2 pages:19-27 ispartof: location:England status: published

Published
2019

15. C9orf72 and UNC13A are shared risk loci for ALS and FTD: a genome-wide meta-analysis

Author

Diekstra, Frank P., Van Deerlin, Vivianna M., van Swieten, John C., Al-Chalabi, Ammar, Ludolph, Albert C., Weishaupt, Jochen H., Hardiman, Orla, Landers, John E., Brown, Robert H., van Es, Michael A., Pasterkamp, R. Jeroen, Koppers, Max, Andersen, Peter M., Estrada, Karol, Rivadeneira, Fernando, Hofman, Albert, Uitterlinden, André G., van Damme, Philip, Melki, Judith, Meininger, Vincent, Shatunov, Aleksey, Shaw, Christopher E., Leigh, P. Nigel, Shaw, Pamela J., Morrison, Karen E., Fogh, Isabella, Chiò, Adriano, Traynor, Bryan J., Czell, David, Weber, Markus, Heutink, Peter, de Bakker, Paul I. W., Silani, Vincenzo, Robberecht, Wim, van den Berg, Leonard H., and Veldink, Jan H.

Subjects
DNA Repeat Expansion, C9orf72 Protein, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, Mutation, Humans, Proteins, Nerve Tissue Proteins, Chromosomes, Human, Pair 9, Chromosomes, Human, Pair 19, Polymorphism, Single Nucleotide, Article, Genome-Wide Association Study
Abstract

Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD.We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes.Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 × 10(-12) ) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 × 10(-11) ) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 × 10(-7) ) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 × 10(-7) ).We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP.

Published
2014

16. The effect of SMN gene dosage on ALS risk and disease severity

Author

Vincenzo Silani, Mamede de Carvalho, Nicola Ticozzi, Joke J.F.A. van Vugt, Kristel R. van Eijk, Patrick Vourc'h, Markus Weber, Wouter van Rheenen, Kevin P. Kenna, Christopher Shaw, Wim Robberecht, Philippe Couratier, Mònica Povedano, Jonathan D. Glass, Pamela J. Shaw, Ramona A. J. Zwamborn, Ammar Al-Chalabi, John Landers, Michael A. Eberle, Michael A. van Es, Xiao Chen, Leonard H. van den Berg, Brendan J. Kenna, Philippe Corcia, Karen E. Morrison, Marc Gotkine, Russell McLaughin, Peter M. Andersen, Matthieu Moisse, Philip Van Damme, Rick A.A. van der Spek, Jesus S. Mora Pardina, Orla Hardiman, Vivian E. Drory, Jan H. Veldink, Nazli Basak, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Moisse, Matthieu, Zwamborn, Ramona A. J., van Vugt, Joke, van Der Spek, Rick, van Rheenen, Wouter, Kenna, Brendan, Van Eijk, Kristel, Kenna, Kevin, Corcia, Philippe, Couratier, Philippe, Vourc'h, Patrick, Hardiman, Orla, McLaughin, Russell, Gotkine, Marc, Drory, Vivian, Ticozzi, Nicola, Silani, Vincenzo, de Carvalho, Mamede, Mora Pardina, Jesus S., Povedano, Monica, Andersen, Peter M., Weber, Markus, Chen, Xiao, Eberle, Michael A., Al-Chalabi, Ammar, Shaw, Chris, Shaw, Pamela J., Morrison, Karen E., Landers, John E., Glass, Jonathan D., Robberecht, Wim, van Es, Michael, van den Berg, Leonard, Veldink, Jan, Van Damme, Philip, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Université de Leuven, Katholiek Universiteit Leuven, Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Service de Neurologie [CHU Limoges], CHU Limoges, UMR U 1253, Department of Neurology, The Adelaide and Meath Hospital, Trinity College Dublin, Trinity College, Trinity College Dublin, Tel Aviv Sourasky Medical Center [Te Aviv], Department of Neurology, IRCCS San Raffaele, Milano, Université de Lisbonne, Sant Rafael Hospital, Umeå University Hospital, Umea University Hospital, Illumina Incorporated [San Diego, CA, USA], Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield [Sheffield], Queen's University [Belfast] (QUB), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Emory University School of Medicine, Emory University [Atlanta, GA], University Hospitals Leuven [Leuven], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), Grelier, Elisabeth, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-CHU Limoges-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST)

Subjects
0301 basic medicine, Male, Neurologi, Survival of Motor Neuron 2 Protein/genetics, Clinical Neurology, Gene Dosage, SMN1, Bioinformatics, Logistic regression, Severity of Illness Index, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, medicine, Survival of Motor Neuron 1 Protein/genetics, Humans, Amyotrophic lateral sclerosis, Gene, Research Articles, Whole genome sequencing, Science & Technology, Whole Genome Sequencing, business.industry, Project MinE, Amyotrophic Lateral Sclerosis, Neurosciences, Case-control study, Reproducibility of Results, Survival of motor neuron, Amyotrophic Lateral Sclerosis/genetics, medicine.disease, Survival of Motor Neuron 1 Protein, 3. Good health, nervous system diseases, Survival of Motor Neuron 2 Protein, 030104 developmental biology, Neurology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Medicine, Clinical neurology, Neurosciences & Neurology, Neurology (clinical), business, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Research Article
Abstract

Objective: the role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency. Methods: in this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data. Results: the copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63). Interpretation: in our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies., European Union (EU); Horizon 2020; European Research Council (ERC); Research and Innovation Programme; EScORIAL; IWT; FWO-Vlaanderen; United Kingdom Medical Research Council; Neurodegenerative Disease Research (JPND); Netherlands; ZONMW; BRAIN-MEND; NIH/NINDS; Italian Ministry of Health; Fondazione Regionale per la Ricerca Biomedica Regione Lombardia; Science Foundation Ireland; ALS Liga Belgie; National Lottery of Belgium; KU Leuven Opening the Future Fund; E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders; ALS Foundation Netherlands; PPP Allowance; Motor Neurone Disease Association; National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre; Fondazione Italiana di Ricerca per la SLA - AriSLA; Exomefals; Novals; ALS Association; E-RARE JTC Project Repetomics

Published
2021

17. STrengthening the Reporting Of Pharmacogenetic Studies: Development of the STROPS guideline

Author

Marty Chaplin, Jamie J. Kirkham, Kerry Dwan, Derek J. Sloan, Geraint Davies, Andrea L. Jorgensen, Irma Aguilar-Delfín, José A G Agúndez, Sophie M Argon, M J Arranz, Derrick A Bennett, Stefan Böhringer, Lawrence Brody, Ingolf Cascorbi, Erika Cecchin, Mandy Crommentuijn-van Rhenen, Ann K Daly, Nur Aizati Athirah Daud, Jorge Duconge, Chiara Fabbri, Alison Fitches, Andrea Gaedigk, Donato Gemmati, Claudia Maria Dan Hawcutt, Rachel Huddart, Evelyne Jacqz-Aigrain, Slobodan M Janković, Theodora Katsila, Gideon Koren, Beata S Lipska-Ziętkiewicz, Thomas Liehr, A H Maitland-van der Zee, Lisanne E N Manson, Martin H Maurer, Juan Eduardo Megías-Vericat, Taichi Ochi, Daniel J O'Connor, Laura B Ramsey, Gad Rennert, Francesco Rucci, Gaetano Santulli, Aris Saoulidis, Rashmi R Shah, Alessandro Serretti, Andrew Somogyi, Gere Sunder-Plassmann, Virginia Boso-Ribelles, Caroline F Thorn, Evangelia Eirini Tsermpini, Satyanarayana Chakradhara Rao Uppugunduri, Michael A van Es, Magdalena Zarowiecki, University of St Andrews. School of Medicine, University of St Andrews. Infection and Global Health Division, Chaplin, Marty, Kirkham, Jamie J., Dwan, Kerry, Sloan, Derek J., Davies, Geraint, Jorgensen, Andrea L., Aguilar-Delfín, Irma, G Agúndez, José A, M Argon, Sophie, J Arranz, M, A Bennett, Derrick, Böhringer, Stefan, Brody, Lawrence, Cascorbi, Ingolf, Cecchin, Erika, Crommentuijn-van Rhenen, Mandy, K Daly, Ann, Aizati Athirah Daud, Nur, Duconge, Jorge, Fabbri, Chiara, Fitches, Alison, Gaedigk, Andrea, Gemmati, Donato, Maria Dan Hawcutt, Claudia, Huddart, Rachel, Jacqz-Aigrain, Evelyne, M Janković, Slobodan, Katsila, Theodora, Koren, Gideon, S Lipska-Ziętkiewicz, Beata, Liehr, Thoma, H Maitland-van der Zee, A, N Manson, Lisanne E, H Maurer, Martin, Eduardo Megías-Vericat, Juan, Ochi, Taichi, J O'Connor, Daniel, B Ramsey, Laura, Rennert, Gad, Rucci, Francesco, Santulli, Gaetano, Saoulidis, Ari, R Shah, Rashmi, Serretti, Alessandro, Somogyi, Andrew, Sunder-Plassmann, Gere, Boso-Ribelles, Virginia, F Thorn, Caroline, Eirini Tsermpini, Evangelia, Chakradhara Rao Uppugunduri, Satyanarayana, A van Es, Michael, and Zarowiecki, Magdalena

Subjects
Male, Delphi Technique, Delphi method, Surveys, 030204 cardiovascular system & hematology, Guidelines and Guidance, Mathematical and Statistical Techniques, 0302 clinical medicine, Surveys and Questionnaires, Medicine and Health Sciences, 030212 general & internal medicine, Statistics, Politics, Stakeholder, Genomics, General Medicine, Research Assessment, Metaanalysis, Middle Aged, Checklist, Systematic review, Research Design, Physical Sciences, Research Reporting Guidelines, Medicine, Engineering and Technology, Female, Goals, Biotechnology, Adult, RM, medicine.medical_specialty, Drug Research and Development, Consensus, Systematic Reviews, MEDLINE, Bioengineering, Research and Analysis Methods, 03 medical and health sciences, Genomic Medicine, Stakeholder Participation, Genetics, medicine, Humans, Statistical Methods, Genetic Association Studies, Pharmacology, Publishing, Survey Research, business.industry, Biology and Life Sciences, DAS, Guideline, United Kingdom, RM Therapeutics. Pharmacology, Pharmacogenomic Testing, Pharmacogenetics, Sample size determination, Family medicine, Pharmacogenomics, business, Mathematics
Abstract

Background Large sample sizes are often required to detect statistically significant associations between pharmacogenetic markers and treatment response. Meta-analysis may be performed to synthesize data from several studies, increasing sample size and, consequently, power to detect significant genetic effects. However, performing robust synthesis of data from pharmacogenetic studies is often challenging because of poor reporting of key data in study reports. There is currently no guideline for the reporting of pharmacogenetic studies that has been developed using a widely accepted robust methodology. The objective of this project was to develop the STrengthening the Reporting Of Pharmacogenetic Studies (STROPS) guideline. Methods and findings We established a preliminary checklist of reporting items to be considered for inclusion in the guideline. We invited representatives of key stakeholder groups to participate in a 2-round Delphi survey. A total of 52 individuals participated in both rounds of the survey, scoring items with regards to their importance for inclusion in the STROPS guideline. We then held a consensus meeting, at which 8 individuals considered the results of the Delphi survey and voted on whether each item ought to be included in the final guideline. The STROPS guideline consists of 54 items and is accompanied by an explanation and elaboration document. The guideline contains items that are particularly important in the field of pharmacogenetics, such as the drug regimen of interest and whether adherence to treatment was accounted for in the conducted analyses. The guideline also requires that outcomes be clearly defined and justified, because in pharmacogenetic studies, there may be a greater number of possible outcomes than in other types of study (for example, disease–gene association studies). A limitation of this project is that our consensus meeting involved a small number of individuals, the majority of whom are based in the United Kingdom. Conclusions Our aim is for the STROPS guideline to improve the transparency of reporting of pharmacogenetic studies and also to facilitate the conduct of high-quality systematic reviews and meta-analyses. We encourage authors to adhere to the STROPS guideline when publishing pharmacogenetic studies., Marty Chaplin and co-authors recount the development of a guideline for reporting pharmacogenetic studies.

Published
2020

18. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Aude Nicolas, Kevin P. Kenna, Alan E. Renton, Nicola Ticozzi, Faraz Faghri, Ruth Chia, Janice A. Dominov, Brendan J. Kenna, Mike A. Nalls, Pamela Keagle, Alberto M. Rivera, Wouter van Rheenen, Natalie A. Murphy, Joke J.F.A. van Vugt, Joshua T. Geiger, Rick A. Van der Spek, Hannah A. Pliner, null Shankaracharya, Bradley N. Smith, Giuseppe Marangi, Simon D. Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, Gabriele Mora, Andrea Calvo, Letizia Mazzini, Nilo Riva, Jessica Mandrioli, Claudia Caponnetto, Stefania Battistini, Paolo Volanti, Vincenzo La Bella, Francesca L. Conforti, Giuseppe Borghero, Sonia Messina, Isabella L. Simone, Francesca Trojsi, Fabrizio Salvi, Francesco O. Logullo, Sandra D’Alfonso, Lucia Corrado, Margherita Capasso, Luigi Ferrucci, Cristiane de Araujo Martins Moreno, Sitharthan Kamalakaran, David B. Goldstein, Aaron D. Gitler, Tim Harris, Richard M. Myers, Hemali Phatnani, Rajeeva Lochan Musunuri, Uday Shankar Evani, Avinash Abhyankar, Michael C. Zody, Julia Kaye, Steven Finkbeiner, Stacia K. Wyman, Alex LeNail, Leandro Lima, Ernest Fraenkel, Clive N. Svendsen, Leslie M. Thompson, Jennifer E. Van Eyk, James D. Berry, Timothy M. Miller, Stephen J. Kolb, Merit Cudkowicz, Emily Baxi, Michael Benatar, J. Paul Taylor, Evadnie Rampersaud, Gang Wu, Joanne Wuu, Giuseppe Lauria, Federico Verde, Isabella Fogh, Cinzia Tiloca, Giacomo P. Comi, Gianni Sorarù, Cristina Cereda, Philippe Corcia, Hannu Laaksovirta, Liisa Myllykangas, Lilja Jansson, Miko Valori, John Ealing, Hisham Hamdalla, Sara Rollinson, Stuart Pickering-Brown, Richard W. Orrell, Katie C. Sidle, Andrea Malaspina, John Hardy, Andrew B. Singleton, Janel O. Johnson, Sampath Arepalli, Peter C. Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, Safa Al-Sarraj, Andrew King, Claire Troakes, Caroline Vance, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, José Luis Muñoz-Blanco, Dena G. Hernandez, Jinhui Ding, J. Raphael Gibbs, Sonja W. Scholz, Mary Kay Floeter, Roy H. Campbell, Francesco Landi, Robert Bowser, Stefan M. Pulst, John M. Ravits, Daniel J.L. MacGowan, Janine Kirby, Erik P. Pioro, Roger Pamphlett, James Broach, Glenn Gerhard, Travis L. Dunckley, Christopher B. Brady, Neil W. Kowall, Juan C. Troncoso, Isabelle Le Ber, Kevin Mouzat, Serge Lumbroso, Terry D. Heiman-Patterson, Freya Kamel, Ludo Van Den Bosch, Robert H. Baloh, Tim M. Strom, Thomas Meitinger, Aleksey Shatunov, Kristel R. Van Eijk, Mamede de Carvalho, Maarten Kooyman, Bas Middelkoop, Matthieu Moisse, Russell L. McLaughlin, Michael A. Van Es, Markus Weber, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Karen E. Morrison, A. Nazli Basak, Jesús S. Mora, Vivian E. Drory, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Orla Hardiman, Kelly L. Williams, Jennifer A. Fifita, Garth A. Nicholson, Ian P. Blair, Guy A. Rouleau, Jesús Esteban-Pérez, Alberto García-Redondo, Ammar Al-Chalabi, Ekaterina Rogaeva, Lorne Zinman, Lyle W. Ostrow, Nicholas J. Maragakis, Jeffrey D. Rothstein, Zachary Simmons, Johnathan Cooper-Knock, Alexis Brice, Stephen A. Goutman, Eva L. Feldman, Summer B. Gibson, Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip Van Damme, Wim Robberecht, Pietro Fratta, Mario Sabatelli, Christian Lunetta, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, William Camu, John Q. Trojanowski, Vivianna M. Van Deerlin, Robert H. Brown, Leonard H. van den Berg, Jan H. Veldink, Matthew B. Harms, Jonathan D. Glass, David J. Stone, Pentti Tienari, Vincenzo Silani, Adriano Chiò, Christopher E. Shaw, Bryan J. Traynor, John E. Landers, Isabella Simone, Giancarlo Logroscino, Ilaria Bartolomei, Maria Rita Murru, Emanuela Costantino, Carla Pani, Roberta Puddu, Carla Caredda, Valeria Piras, Stefania Tranquilli, Stefania Cuccu, Daniela Corongiu, Maurizio Melis, Antonio Milia, Francesco Marrosu, Maria Giovanna Marrosu, Gianluca Floris, Antonino Cannas, Gianluigi Mancardi, Paola Origone, Paola Mandich, Sebastiano Cavallaro, Kalliopi Marinou, Riccardo Sideri, Silvana Penco, Lorena Mosca, Giuseppe Lauria Pinter, Massimo Corbo, Paola Carrera, Nicola Fini, Antonio Fasano, Lucio Tremolizzo, Alessandro Arosio, Carlo Ferrarese, Gioacchino Tedeschi, Maria Rosaria Monsurrò, Giovanni Piccirillo, Cinzia Femiano, Anna Ticca, Enzo Ortu, Rossella Spataro, Tiziana Colletti, Marcella Zollino, Amelia Conte, Marco Luigetti, Serena Lattante, Marialuisa Santarelli, Antonio Petrucci, Maura Pugliatti, Angelo Pirisi, Leslie D. Parish, Patrizia Occhineri, Fabio Giannini, Claudia Ricci, Michele Benigni, Tea B. Cau, Daniela Loi, Cristina Moglia, Maura Brunetti, Marco Barberis, Gabriella Restagno, Federico Casale, Giuseppe Marrali, Giuseppe Fuda, Irene Ossola, Stefania Cammarosano, Antonio Canosa, Antonio Ilardi, Umberto Manera, Maurizio Grassano, Raffaella Tanel, Fabrizio Pisano, Neil A. Shneider, Stephen Goutman, Siddharthan Chandran, Suvankar Pal, George Manousakis, Stanley H. Appel, Ericka Simpson, Leo Wang, Summer Gibson, Richard Bedlack, David Lacomis, Dhruv Sareen, Alexander Sherman, Lucie Bruijn, Michelle Penny, Andrew S. Allen, Stanley Appel, Richard S. Bedlack, Braden E. Boone, Robert Brown, John P. Carulli, Alessandra Chesi, Wendy K. Chung, Elizabeth T. Cirulli, Gregory M. Cooper, Julien Couthouis, Aaron G. Day-Williams, Patrick A. Dion, Yujun Han, Sebastian D. Hayes, Angela L. Jones, Jonathan Keebler, Brian J. Krueger, Brittany N. Lasseigne, Shawn E. Levy, Yi-Fan Lu, Tom Maniatis, Slavé Petrovski, Alya R. Raphael, Zhong Ren, Katherine B. Sims, John F. Staropoli, Lindsay L. Waite, Quanli Wang, Jack R. Wimbish, Winnie W. Xin, Justin Kwan, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Noah Zaitlen, Gregory A. Cox, Steve Finkbeiner, Efthimios Dardiotis, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos A. Patsopoulos, Joshua Dubnau, Avindra Nath, Stacia Wyman, Alexander LeNail, Jenny Van Eyk, Stephan Züchner, Rebecca Schule, Jacob McCauley, Sumaira Hussain, Anne Cooley, Marielle Wallace, Christine Clayman, Richard Barohn, Jeffrey Statland, John Ravits, Andrea Swenson, Carlayne Jackson, Jaya Trivedi, Shaida Khan, Jonathan Katz, Liberty Jenkins, Ted Burns, Kelly Gwathmey, James Caress, Corey McMillan, Lauren Elman, Erik Pioro, Jeannine Heckmann, Yuen So, David Walk, Samuel Maiser, Jinghui Zhang, Fabiola De Marchi, Stefania Corti, Mauro Ceroni, Gabriele Siciliano, Massimiliano Filosto, Maurizio Inghilleri, Silvia Peverelli, Claudia Colombrita, Barbara Poletti, Luca Maderna, Roberto Del Bo, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Viviana Pensato, Barbara Castellotti, Vincent Meininger, Gérard Besson, Emmeline Lagrange, Pierre Clavelou, Nathalie Guy, Philippe Couratier, Patrick Vourch, Véronique Danel, Emilien Bernard, Gwendal Lemasson, Ahmad Al Kheifat, Peter Andersen, Adriano Chio, Jonathan Cooper-Knock, Annelot Dekker, Vivian Drory, Alberto Garcia Redondo, Marc Gotkine, Winston Hide, Alfredo Iacoangeli, Jonathan Glass, Kevin Kenna, Matthew Kiernan, John Landers, Russell McLaughlin, Jonathan Mill, Miguel Mitne Neto, Mattieu Moisse, Jesus Mora Pardina, Karen Morrison, Stephen Newhouse, Susana Pinto, Sara Pulit, Pamela Shaw, Chris Shaw, William Sproviero, Gijs Tazelaar, Philip van Damme, Leonard van den Berg, Rick van der Spek, Kristel van Eijk, Michael van Es, Joke van Vugt, Jan Veldink, Mayana Zatz, Denis C. Bauer, Natalie A. Twine, Department of Neurosciences, Pentti Tienari / Principal Investigator, Neurologian yksikkö, Research Programs Unit, Clinicum, Research Programme for Molecular Neurology, University of Helsinki, Medicum, Department of Pathology, HUS Neurocenter, Nicolas A., Kenna K.P., Renton A.E., Ticozzi N., Faghri F., Chia R., Dominov J.A., Kenna B.J., Nalls M.A., Keagle P., Rivera A.M., van Rheenen W., Murphy N.A., van Vugt J.J.F.A., Geiger J.T., Van der Spek R.A., Pliner H.A., Shankaracharya, Smith B.N., Marangi G., Topp S.D., Abramzon Y., Gkazi A.S., Eicher J.D., Kenna A., Logullo F.O., Simone I.L., Logroscino G., Salvi F., Bartolomei I., Borghero G., Murru M.R., Costantino E., Pani C., Puddu R., Caredda C., Piras V., Tranquilli S., Cuccu S., Corongiu D., Melis M., Milia A., Marrosu F., Marrosu M.G., Floris G., Cannas A., Capasso M., Caponnetto C., Mancardi G., Origone P., Mandich P., Conforti F.L., Cavallaro S., Mora G., Marinou K., Sideri R., Penco S., Mosca L., Lunetta C., Pinter G.L., Corbo M., Riva N., Carrera P., Volanti P., Mandrioli J., Fini N., Fasano A., Tremolizzo L., Arosio A., Ferrarese C., Trojsi F., Tedeschi G., Monsurro M.R., Piccirillo G., Femiano C., Ticca A., Ortu E., La Bella V., Spataro R., Colletti T., Sabatelli M., Zollino M., Conte A., Luigetti M., Lattante S., Santarelli M., Petrucci A., Pugliatti M., Pirisi A., Parish L.D., Occhineri P., Giannini F., Battistini S., Ricci C., Benigni M., Cau T.B., Loi D., Calvo A., Moglia C., Brunetti M., Barberis M., Restagno G., Casale F., Marrali G., Fuda G., Ossola I., Cammarosano S., Canosa A., Ilardi A., Manera U., Grassano M., Tanel R., Pisano F., Mazzini L., Messina S., D'Alfonso S., Corrado L., Ferrucci L., Harms M.B., Goldstein D.B., Shneider N.A., Goutman S.A., Simmons Z., Miller T.M., Chandran S., Pal S., Manousakis G., Appel S.H., Simpson E., Wang L., Baloh R.H., Gibson S.B., Bedlack R., Lacomis D., Sareen D., Sherman A., Bruijn L., Penny M., Moreno C.D.A.M., Kamalakaran S., Allen A.S., Boone B.E., Brown R.H., Carulli J.P., Chesi A., Chung W.K., Cirulli E.T., Cooper G.M., Couthouis J., Day-Williams A.G., Dion P.A., Gitler A.D., Glass J.D., Han Y., Harris T., Hayes S.D., Jones A.L., Keebler J., Krueger B.J., Lasseigne B.N., Levy S.E., Lu Y.-F., Maniatis T., McKenna-Yasek D., Myers R.M., Petrovski S., Pulst S.M., Raphael A.R., Ravits J.M., Ren Z., Rouleau G.A., Sapp P.C., Sims K.B., Staropoli J.F., Waite L.L., Wang Q., Wimbish J.R., Xin W.W., Phatnani H., Kwan J., Broach J., Arcila-Londono X., Lee E.B., Van Deerlin V.M., Fraenkel E., Ostrow L.W., Baas F., Zaitlen N., Berry J.D., Malaspina A., Fratta P., Cox G.A., Thompson L.M., Finkbeiner S., Dardiotis E., Hornstein E., MacGowan D.J.L., Heiman-Patterson T., Hammell M.G., Patsopoulos N.A., Dubnau J., Nath A., Musunuri R.L., Evani U.S., Abhyankar A., Zody M.C., Kaye J., Wyman S.K., LeNail A., Lima L., Rothstein J.D., Svendsen C.N., Van Eyk J.E., Maragakis N.J., Kolb S.J., Cudkowicz M., Baxi E., Benatar M., Taylor J.P., Wu G., Rampersaud E., Wuu J., Rademakers R., Zuchner S., Schule R., McCauley J., Hussain S., Cooley A., Wallace M., Clayman C., Barohn R., Statland J., Swenson A., Jackson C., Trivedi J., Khan S., Katz J., Jenkins L., Burns T., Gwathmey K., Caress J., McMillan C., Elman L., Pioro E.P., Heckmann J., So Y., Walk D., Maiser S., Zhang J., Silani V., Gellera C., Ratti A., Taroni F., Lauria G., Verde F., Fogh I., Tiloca C., Comi G.P., Soraru G., Cereda C., De Marchi F., Corti S., Ceroni M., Siciliano G., Filosto M., Inghilleri M., Peverelli S., Colombrita C., Poletti B., Maderna L., Del Bo R., Gagliardi S., Querin G., Bertolin C., Pensato V., Castellotti B., Camu W., Mouzat K., Lumbroso S., Corcia P., Meininger V., Besson G., Lagrange E., Clavelou P., Guy N., Couratier P., Vourch P., Danel V., Bernard E., Lemasson G., Laaksovirta H., Myllykangas L., Jansson L., Valori M., Ealing J., Hamdalla H., Rollinson S., Pickering-Brown S., Orrell R.W., Sidle K.C., Hardy J., Singleton A.B., Johnson J.O., Arepalli S., Polak M., Asress S., Al-Sarraj S., King A., Troakes C., Vance C., de Belleroche J., ten Asbroek A.L.M.A., Munoz-Blanco J.L., Hernandez D.G., Ding J., Gibbs J.R., Scholz S.W., Floeter M.K., Campbell R.H., Landi F., Bowser R., Kirby J., Pamphlett R., Gerhard G., Dunckley T.L., Brady C.B., Kowall N.W., Troncoso J.C., Le Ber I., Heiman-Patterson T.D., Kamel F., Van Den Bosch L., Strom T.M., Meitinger T., Shatunov A., Van Eijk K.R., de Carvalho M., Kooyman M., Middelkoop B., Moisse M., McLaughlin R.L., Van Es M.A., Weber M., Boylan K.B., Van Blitterswijk M., Morrison K.E., Basak A.N., Mora J.S., Drory V.E., Shaw P.J., Turner M.R., Talbot K., Hardiman O., Williams K.L., Fifita J.A., Nicholson G.A., Blair I.P., Esteban-Perez J., Garcia-Redondo A., Al-Chalabi A., Al Kheifat A., Andersen P.M., Chio A., Cooper-Knock J., Dekker A., Redondo A.G., Gotkine M., Hide W., Iacoangeli A., Kiernan M., Landers J.E., Mill J., Neto M.M., Pardina J.M., Newhouse S., Pinto S., Pulit S., Robberecht W., Shaw C., Sproviero W., Tazelaar G., Van Damme P., van den Berg L.H., van Vugt J., Veldink J.H., Zatz M., Bauer D.C., Twine N.A., Rogaeva E., Zinman L., Brice A., Feldman E.L., Ludolph A.C., Weishaupt J.H., Trojanowski J.Q., Stone D.J., Tienari P., Shaw C.E., Traynor B.J., ITALSGEN Consortium, Genomic Translation ALS Care GTAC, ALS Sequencing Consortium, NYGC ALS Consortium, Answer ALS Fdn, Clinical Res ALS Related Disorders, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consor, Medical Research Council (MRC), ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Università cattolica del Sacro Cuore [Roma] (Unicatt), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Lunar and Planetary Laboratory [Tucson] (LPL), University of Arizona, Università degli studi di Torino (UNITO), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), New York Genome Center [New York], New York Genome Center, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), St Jude Children's Research Hospital, Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University College of London [London] (UCL), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), King‘s College London, University of New Haven [Connecticut], Princeton University, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), University Medical Center [Utrecht], Deutsches Forschungszentrum für Künstliche Intelligenz GmbH = German Research Center for Artificial Intelligence (DFKI), Mayo Clinic [Jacksonville], Trinity College Dublin, Maurice Wohl Clinical Neuroscience Institut, Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Repositório da Universidade de Lisboa, Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P, Renton, Alan E, Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A, Kenna, Brendan J, Nalls, Mike A, Keagle, Pamela, Rivera, Alberto M, van Rheenen, Wouter, Murphy, Natalie A, van Vugt, Joke J F A, Geiger, Joshua T, Van der Spek, Rick A, Pliner, Hannah A, Shankaracharya, Null, Smith, Bradley N, Marangi, Giuseppe, Topp, Simon D, Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D, Kenna, Aoife, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L, Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L, Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O, D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Logullo, Fo, Murru, Mr, Marrosu, Mg, Conforti, Fl, Pinter, Gl, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Parish, Ld, Cau, Tb, Moreno, Cristiane de Araujo Martin, Kamalakaran, Sitharthan, Goldstein, David B, Gitler, Aaron D, Harris, Tim, Myers, Richard M, Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K, Lenail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N, Thompson, Leslie M, Van Eyk, Jennifer E, Berry, James D, Miller, Timothy M, Kolb, Stephen J, Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P, Sorarù, Gianni, Cereda, Cristina, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W, Sidle, Katie C, Malaspina, Andrea, Hardy, John, Singleton, Andrew B, Johnson, Janel O, Arepalli, Sampath, Sapp, Peter C, McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, Baas, Frank, Ten Asbroek, Anneloor L M A, Muñoz-Blanco, José Lui, Hernandez, Dena G, Ding, Jinhui, Gibbs, J Raphael, Scholz, Sonja W, Floeter, Mary Kay, Campbell, Roy H, Landi, Francesco, Bowser, Robert, Pulst, Stefan M, Ravits, John M, Macgowan, Daniel J L, Kirby, Janine, Pioro, Erik P, Pamphlett, Roger, Broach, Jame, Gerhard, Glenn, Dunckley, Travis L, Brady, Christopher B, Kowall, Neil W, Troncoso, Juan C, Le Ber, Isabelle, Mouzat, Kevin, Lumbroso, Serge, Heiman-Patterson, Terry D, Kamel, Freya, Van Den Bosch, Ludo, Baloh, Robert H, Strom, Tim M, Meitinger, Thoma, Shatunov, Aleksey, Van Eijk, Kristel R, de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Ba, Moisse, Matthieu, Mclaughlin, Russell L, Van Es, Michael A, Weber, Marku, Boylan, Kevin B, Van Blitterswijk, Marka, Rademakers, Rosa, Morrison, Karen E, Basak, A Nazli, Mora, Jesús S, Drory, Vivian E, Shaw, Pamela J, Turner, Martin R, Talbot, Kevin, Hardiman, Orla, Williams, Kelly L, Fifita, Jennifer A, Nicholson, Garth A, Blair, Ian P, Rouleau, Guy A, Esteban-Pérez, Jesú, García-Redondo, Alberto, Al-Chalabi, Ammar, Rogaeva, Ekaterina, Zinman, Lorne, Ostrow, Lyle W, Maragakis, Nicholas J, Rothstein, Jeffrey D, Simmons, Zachary, Cooper-Knock, Johnathan, Brice, Alexi, Goutman, Stephen A, Feldman, Eva L, Gibson, Summer B, Taroni, Franco, Ratti, Antonia, Gellera, Cinzia, Van Damme, Philip, Robberecht, Wim, Fratta, Pietro, Sabatelli, Mario, Lunetta, Christian, Ludolph, Albert C, Andersen, Peter M, Weishaupt, Jochen H, Camu, William, Trojanowski, John Q, Van Deerlin, Vivianna M, Brown, Robert H, van den Berg, Leonard H, Veldink, Jan H, Harms, Matthew B, Glass, Jonathan D, Stone, David J, Tienari, Pentti, Silani, Vincenzo, Chiò, Adriano, Shaw, Christopher E, Traynor, Bryan J, Landers, John E, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Male, Als gene, Genome-wide association study, FAMILIAL ALS, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, 0302 clinical medicine, 80 and over, Psychology, Aetiology, Aged, 80 and over, 0303 health sciences, French ALS Consortium, Kinesin, KINESIN HEAVY-CHAIN, Cognitive Sciences, Human, Hereditary spastic paraplegia, Neuroscience(all), Single-nucleotide polymorphism, TARGETED DISRUPTION, Article, 03 medical and health sciences, Genetics, Humans, Amino Acid Sequence, Loss function, Aged, HEXANUCLEOTIDE REPEAT, Neuroscience (all), MUTATIONS, Amyotrophic Lateral Sclerosis, 3112 Neurosciences, 1702 Cognitive Science, medicine.disease, ITALSGEN Consortium, Answer ALS Foundation, 030104 developmental biology, ALS Sequencing Consortium, Human medicine, 1109 Neurosciences, 030217 neurology & neurosurgery, 0301 basic medicine, [SDV]Life Sciences [q-bio], Kinesins, Neurodegenerative, Genetic analysis, Genome, AMYOTROPHIC-LATERAL-SCLEROSIS, 3124 Neurology and psychiatry, Cohort Studies, Pathogenesis, Loss of Function Mutation, Missense mutation, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, NYGC ALS Consortium, General Neuroscience, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, Middle Aged, Phenotype, Settore MED/26 - NEUROLOGIA, Neurological, Project MinE ALS Sequencing Consortium, Female, Adult, Biology, GENOTYPE IMPUTATION, Genome-Wide Association Study, Young Adult, NO, Rare Diseases, medicine, SLAGEN Consortium, Gene, 030304 developmental biology, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Neurology & Neurosurgery, Human Genome, Neurosciences, AXONAL-TRANSPORT, Brain Disorders, Family member, DNA-DAMAGE, MOTOR-NEURONS, 3111 Biomedicine, Cohort Studie, Genomic Translation for ALS Care (GTAC) Consortium, Amyotrophic Lateral Sclerosi
Abstract

© 2018 Elsevier Inc., To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Published
2018

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