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1. ATAXIN-2 intermediate-length polyglutamine expansions elicit ALS-associated metabolic and immune phenotypes

Author

Vieira de Sá, Renata, Sudria-Lopez, Emma, Cañizares Luna, Marta, Harschnitz, Oliver, van den Heuvel, Dianne M. A., Kling, Sandra, Vonk, Danielle, Westeneng, Henk-Jan, Karst, Henk, Bloemenkamp, Lauri, Varderidou-Minasian, Suzy, Schlegel, Domino K., Mars, Mayte, Broekhoven, Mark H., van Kronenburg, Nicky C. H., Adolfs, Youri, Vangoor, Vamshidhar R., de Jongh, Rianne, Ljubikj, Tijana, Peeters, Lianne, Seeler, Sabine, Mocholi, Enric, Basak, Onur, Gordon, David, Giuliani, Fabrizio, Verhoeff, Tessa, Korsten, Giel, Calafat Pla, Teresa, Venø, Morten T., Kjems, Jørgen, Talbot, Kevin, van Es, Michael A., Veldink, Jan H., van den Berg, Leonard H., Zelina, Pavol, and Pasterkamp, R. Jeroen

Published
2024
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2. 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

4. Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

Author

Al Khleifat, Ahmad, Iacoangeli, Alfredo, van Vugt, Joke J. F. A., Bowles, Harry, Moisse, Matthieu, Zwamborn, Ramona A. J., van der Spek, Rick A. A., Shatunov, Aleksey, Cooper-Knock, Johnathan, Topp, Simon, Byrne, Ross, Gellera, Cinzia, López, Victoria, Jones, Ashley R., Opie-Martin, Sarah, Vural, Atay, Campos, Yolanda, van Rheenen, Wouter, Kenna, Brendan, Van Eijk, Kristel R., Kenna, Kevin, Weber, Markus, Smith, Bradley, Fogh, Isabella, Silani, Vincenzo, Morrison, Karen E., Dobson, Richard, van Es, Michael A., McLaughlin, Russell L., Vourc’h, Patrick, Chio, Adriano, Corcia, Philippe, de Carvalho, Mamede, Gotkine, Marc, Panades, Monica P., Mora, Jesus S., Shaw, Pamela J., Landers, John E., Glass, Jonathan D., Shaw, Christopher E., Basak, Nazli, Hardiman, Orla, Robberecht, Wim, Van Damme, Philip, van den Berg, Leonard H., Veldink, Jan H., and Al-Chalabi, Ammar

Published
2022
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5. Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial

Author

Willemse, Sean W., Roes, Kit C. B., Van Damme, Philip, Hardiman, Orla, Ingre, Caroline, Povedano, Monica, Wray, Naomi R., Gijzen, Marleen, de Pagter, Mirjam S., Demaegd, Koen C., Janse, Annemarie F. C., Vink, Roel G., Sleutjes, Boudewijn T. H. M., Chiò, Adriano, Corcia, Philippe, Reviers, Evy, Al-Chalabi, Ammar, Kiernan, Matthew C., van den Berg, Leonard H., van Es, Michael A., and van Eijk, Ruben P. A.

Published
2022
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6. Assessment of risk of ALS conferred by the GGGGCC hexanucleotide repeat expansion in C9orf72 among first-degree relatives of patients with ALS carrying the repeat expansion

Author

Datamanagement Team 1, Opleiding Neurologie, Projectafdeling ALS, Brain, Neurologen, Neuromuscular Disorders, Biostatistiek Onderzoek, Neurogenetica, Genetic Risks, Van Wijk, Iris F., Van Eijk, Ruben P.A., Van Boxmeer, Loes, Westeneng, Henk Jan, Van Es, Michael A., Van Rheenen, Wouter, Van Den Berg, Leonard H., Eijkemans, Marinus J.C., Veldink, Jan H., Datamanagement Team 1, Opleiding Neurologie, Projectafdeling ALS, Brain, Neurologen, Neuromuscular Disorders, Biostatistiek Onderzoek, Neurogenetica, Genetic Risks, Van Wijk, Iris F., Van Eijk, Ruben P.A., Van Boxmeer, Loes, Westeneng, Henk Jan, Van Es, Michael A., Van Rheenen, Wouter, Van Den Berg, Leonard H., Eijkemans, Marinus J.C., and Veldink, Jan H.

Published
2024

8. Association Between Hypothalamic Volume and Metabolism, Cognition, and Behavior in Patients With Amyotrophic Lateral Sclerosis

Author

Opleiding Neurologie, Neurologen, Brain, Neuromuscular Disorders, Genetic Risks, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Michielsen, Annebelle, van Veenhuijzen, Kevin, Janse van Mantgem, Mark R., van Es, Michael A., Veldink, Jan H., van Eijk, Ruben P.A., van den Berg, Leonard H., Westeneng, Henk Jan, Opleiding Neurologie, Neurologen, Brain, Neuromuscular Disorders, Genetic Risks, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Michielsen, Annebelle, van Veenhuijzen, Kevin, Janse van Mantgem, Mark R., van Es, Michael A., Veldink, Jan H., van Eijk, Ruben P.A., van den Berg, Leonard H., and Westeneng, Henk Jan

Published
2024

9. ATAXIN-2 intermediate-length polyglutamine expansions elicit ALS-associated metabolic and immune phenotypes

Author

Brain, TN groep Pasterkamp, Opleiding Neurologie, Projectafdeling ALS, TN groep Joëls, Cancer, Regenerative Medicine and Stem Cells, Infection & Immunity, CMM Groep Coffer, Translational Neuroscience, Neurogenetica, In Vivo NMR ISI, Neurologen, Neuromuscular Disorders, Genetic Risks, Vieira de Sá, Renata, Sudria-Lopez, Emma, Cañizares Luna, Marta, Harschnitz, Oliver, van den Heuvel, Dianne M A, Kling, Sandra, Vonk, Danielle, Westeneng, Henk-Jan, Karst, Henk, Bloemenkamp, Lauri, Varderidou-Minasian, Suzy, Schlegel, Domino K, Mars, Mayte, Broekhoven, Mark H, van Kronenburg, Nicky C H, Adolfs, Youri, Vangoor, Vamshidhar R, de Jongh, Rianne, Ljubikj, Tijana, Peeters, Lianne, Seeler, Sabine, Mocholi, Enric, Basak, Onur, Gordon, David, Giuliani, Fabrizio, Verhoeff, Tessa, Korsten, Giel, Calafat Pla, Teresa, Venø, Morten T, Kjems, Jørgen, Talbot, Kevin, van Es, Michael A, Veldink, Jan H, van den Berg, Leonard H, Zelina, Pavol, Pasterkamp, R Jeroen, Brain, TN groep Pasterkamp, Opleiding Neurologie, Projectafdeling ALS, TN groep Joëls, Cancer, Regenerative Medicine and Stem Cells, Infection & Immunity, CMM Groep Coffer, Translational Neuroscience, Neurogenetica, In Vivo NMR ISI, Neurologen, Neuromuscular Disorders, Genetic Risks, Vieira de Sá, Renata, Sudria-Lopez, Emma, Cañizares Luna, Marta, Harschnitz, Oliver, van den Heuvel, Dianne M A, Kling, Sandra, Vonk, Danielle, Westeneng, Henk-Jan, Karst, Henk, Bloemenkamp, Lauri, Varderidou-Minasian, Suzy, Schlegel, Domino K, Mars, Mayte, Broekhoven, Mark H, van Kronenburg, Nicky C H, Adolfs, Youri, Vangoor, Vamshidhar R, de Jongh, Rianne, Ljubikj, Tijana, Peeters, Lianne, Seeler, Sabine, Mocholi, Enric, Basak, Onur, Gordon, David, Giuliani, Fabrizio, Verhoeff, Tessa, Korsten, Giel, Calafat Pla, Teresa, Venø, Morten T, Kjems, Jørgen, Talbot, Kevin, van Es, Michael A, Veldink, Jan H, van den Berg, Leonard H, Zelina, Pavol, and Pasterkamp, R Jeroen

Published
2024

10. Familial motor neuron disease: co-occurrence of PLS and ALS (-FTD)

Author

Opleiding Neurologie, Brain, Genetica Klinische Genetica, Child Health, Neurologen, Genetic Risks, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Neuromuscular Disorders, de Boer, Eva M J, Demaegd, Koen C, de Bie, Charlotte I, Veldink, Jan H, van den Berg, Leonard H, van Es, Michael A, Opleiding Neurologie, Brain, Genetica Klinische Genetica, Child Health, Neurologen, Genetic Risks, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Neuromuscular Disorders, de Boer, Eva M J, Demaegd, Koen C, de Bie, Charlotte I, Veldink, Jan H, van den Berg, Leonard H, and van Es, Michael A

Published
2024

12. 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

14. KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia

Author

Pennings, Maartje, Schouten, Meyke I., van Gaalen, Judith, Meijer, Rowdy P. P., de Bot, Susanne T., Kriek, Marjolein, Saris, Christiaan G. J., van den Berg, Leonard H., van Es, Michael A., Zuidgeest, Dick M. H., Elting, Mariet W., van de Kamp, Jiddeke M., van Spaendonck-Zwarts, Karin Y., Die-Smulders, Christine de, Brilstra, Eva H., Verschuuren, Corien C., de Vries, Bert B. A., Bruijn, Jacques, Sofou, Kalliopi, Duijkers, Floor A., Jaeger, B., Schieving, Jolanda H., van de Warrenburg, Bart P., and Kamsteeg, Erik-Jan

Published
2020
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15. 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

16. Weighted gene co-expression network analysis of the peripheral blood from Amyotrophic Lateral Sclerosis patients

Author

Saris, Christiaan GJ, Horvath, Steve, van Vught, Paul WJ, van Es, Michael A, Blauw, Hylke M, Fuller, Tova F, Langfelder, Peter, DeYoung, Joseph, Wokke, John HJ, Veldink, Jan H, van den Berg, Leonard H, and Ophoff, Roel A

Abstract

Abstract Background Amyotrophic Lateral Sclerosis (ALS) is a lethal disorder characterized by progressive degeneration of motor neurons in the brain and spinal cord. Diagnosis is mainly based on clinical symptoms, and there is currently no therapy to stop the disease or slow its progression. Since access to spinal cord tissue is not possible at disease onset, we investigated changes in gene expression profiles in whole blood of ALS patients. Results Our transcriptional study showed dramatic changes in blood of ALS patients; 2,300 probes (9.4%) showed significant differential expression in a discovery dataset consisting of 30 ALS patients and 30 healthy controls. Weighted gene co-expression network analysis (WGCNA) was used to find disease-related networks (modules) and disease related hub genes. Two large co-expression modules were found to be associated with ALS. Our findings were replicated in a second (30 patients and 30 controls) and third dataset (63 patients and 63 controls), thereby demonstrating a highly significant and consistent association of two large co-expression modules with ALS disease status. Ingenuity Pathway Analysis of the ALS related module genes implicates enrichment of functional categories related to genetic disorders, neurodegeneration of the nervous system and inflammatory disease. The ALS related modules contain a number of candidate genes possibly involved in pathogenesis of ALS. Conclusion This first large-scale blood gene expression study in ALS observed distinct patterns between cases and controls which may provide opportunities for biomarker development as well as new insights into the molecular mechanisms of the disease.

Published
2009

17. 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

19. Whole genome sequencing analysis reveals post-zygotic mutation variability in monozygotic twins discordant for amyotrophic lateral sclerosis

Author

Tazelaar, Gijs H.P., Hop, Paul J., Seelen, Meinie, van Vugt, Joke J.F.A., van Rheenen, Wouter, Kool, Lindy, van Eijk, Kristel R., Gijzen, Marleen, Dooijes, Dennis, Moisse, Matthieu, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Nordin, Angelica, Pardina, Jesus S. Mora, Ravits, John, Al-Chalabi, Ammar, Chio, Adriano, McLaughlin, Russell L., Hardiman, Orla, Van Damme, Philip, de Carvalho, Mamede, Neuwirth, Christoph, Weber, Markus, Andersen, Peter M., van den Berg, Leonard H., Veldink, Jan H., van Es, Michael A., Tazelaar, Gijs H.P., Hop, Paul J., Seelen, Meinie, van Vugt, Joke J.F.A., van Rheenen, Wouter, Kool, Lindy, van Eijk, Kristel R., Gijzen, Marleen, Dooijes, Dennis, Moisse, Matthieu, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Nordin, Angelica, Pardina, Jesus S. Mora, Ravits, John, Al-Chalabi, Ammar, Chio, Adriano, McLaughlin, Russell L., Hardiman, Orla, Van Damme, Philip, de Carvalho, Mamede, Neuwirth, Christoph, Weber, Markus, Andersen, Peter M., van den Berg, Leonard H., Veldink, Jan H., and van Es, Michael A.

Abstract

Amyotrophic lateral sclerosis is a heterogeneous, fatal neurodegenerative disease, characterized by motor neuron loss and in 50% of cases also by cognitive and/or behavioral changes. Mendelian forms of ALS comprise approximately 10-15% of cases. The majority is however considered sporadic, but also with a high contribution of genetic risk factors. To explore the contribution of somatic mutations and/or epigenetic changes to disease risk, we performed whole genome sequencing and methylation analyses using samples from multiple tissues on a cohort of 26 monozygotic twins discordant for ALS, followed by in-depth validation and replication experiments. The results of these analyses implicate several mechanisms in ALS pathophysiology, which include a role for de novo mutations, defects in DNA damage repair and accelerated aging.

Published
2023
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20. Genetic variability in sporadic amyotrophic lateral sclerosis

Author

Van Daele, Sien Hilde, Moisse, Matthieu, van Vugt, Joke J F A, Zwamborn, Ramona A J, van der Spek, Rick, van Rheenen, Wouter, Van Eijk, Kristel, Kenna, Kevin, Corcia, Philippe, Vourc'h, Patrick, Couratier, Philippe, Hardiman, Orla, McLaughin, Russell, Gotkine, Marc, Drory, Vivian, Ticozzi, Nicola, Silani, Vincenzo, Ratti, Antonia, de Carvalho, Mamede, Mora Pardina, Jesús S, Povedano, Monica, Andersen, Peter M., Weber, Markus, Başak, Nazli A., Shaw, Chris, Shaw, Pamela J., Morrison, Karen E., Landers, John E., Glass, Jonathan D., van Es, Michael A., van den Berg, Leonard H., Al-Chalabi, Ammar, Veldink, Jan, Van Damme, Philip, Van Daele, Sien Hilde, Moisse, Matthieu, van Vugt, Joke J F A, Zwamborn, Ramona A J, van der Spek, Rick, van Rheenen, Wouter, Van Eijk, Kristel, Kenna, Kevin, Corcia, Philippe, Vourc'h, Patrick, Couratier, Philippe, Hardiman, Orla, McLaughin, Russell, Gotkine, Marc, Drory, Vivian, Ticozzi, Nicola, Silani, Vincenzo, Ratti, Antonia, de Carvalho, Mamede, Mora Pardina, Jesús S, Povedano, Monica, Andersen, Peter M., Weber, Markus, Başak, Nazli A., Shaw, Chris, Shaw, Pamela J., Morrison, Karen E., Landers, John E., Glass, Jonathan D., van Es, Michael A., van den Berg, Leonard H., Al-Chalabi, Ammar, Veldink, Jan, and Van Damme, Philip

Abstract

With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), there is a surge in gene testing for this disease. Although there is ample experience with gene testing for C9orf72, SOD1, FUS and TARDBP in familial ALS, large studies exploring genetic variation in all ALS-associated genes in sporadic ALS (sALS) are still scarce. Gene testing in a diagnostic setting is challenging, given the complex genetic architecture of sALS, for which there are genetic variants with large and small effect sizes. Guidelines for the interpretation of genetic variants in gene panels and for counselling of patients are lacking. We aimed to provide a thorough characterization of genetic variability in ALS genes by applying the American College of Medical Genetics and Genomics (ACMG) criteria on whole genome sequencing data from a large cohort of 6013 sporadic ALS patients and 2411 matched controls from Project MinE. We studied genetic variation in 90 ALS-associated genes and applied customized ACMG-criteria to identify pathogenic and likely pathogenic variants. Variants of unknown significance were collected as well. In addition, we determined the length of repeat expansions in C9orf72, ATXN1, ATXN2 and NIPA1 using the ExpansionHunter tool. We found C9orf72 repeat expansions in 5.21% of sALS patients. In 50 ALS-associated genes, we did not identify any pathogenic or likely pathogenic variants. In 5.89%, a pathogenic or likely pathogenic variant was found, most commonly in SOD1, TARDBP, FUS, NEK1, OPTN or TBK1. Significantly more cases carried at least one pathogenic or likely pathogenic variant compared to controls (odds ratio 1.75; P-value 1.64 × 10-5). Isolated risk factors in ATXN1, ATXN2, NIPA1 and/or UNC13A were detected in 17.33% of cases. In 71.83%, we did not find any genetic clues. A combination of variants was found in 2.88%. This study provides an inventory of pathogenic and likely pathogenic genetic variation in a large cohort of sALS patients. Overall, we identi

Published
2023
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21. Outcomes after robotic thymectomy in nonthymomatous versus thymomatous patients with acetylcholine-receptor-antibody-associated myasthenia gravis

Author

Marcuse, Florit, Hoeijmakers, Janneke G.J., Hochstenbag, Monique, Hamid, Myrurgia Abdul, Keijzers, Marlies, Mané-Damas, Marina, Martinez-Martinez, Pilar, Verschuuren, Jan, Kuks, Jan, Beekman, Roy, van der Kooi, Anneke J., van Doorn, Pieter, van Es, Michael, Maessen, Jos J.G., De Baets, Marc H.V., Marcuse, Florit, Hoeijmakers, Janneke G.J., Hochstenbag, Monique, Hamid, Myrurgia Abdul, Keijzers, Marlies, Mané-Damas, Marina, Martinez-Martinez, Pilar, Verschuuren, Jan, Kuks, Jan, Beekman, Roy, van der Kooi, Anneke J., van Doorn, Pieter, van Es, Michael, Maessen, Jos J.G., and De Baets, Marc H.V.

Abstract

The aim of this study was to investigate the surgical and long-term neurological outcomes of patients with acetylcholine-receptor-antibody-associated myasthenia gravis (AChR-MG) who underwent robotic thymectomy (RATS). We retrospectively analyzed the clinical-pathological data of all patients with AChR-MG who underwent RATS using the DaVinci® Robotic System at the MUMC+ between April 2004 and December 2018. Follow-up data were collected from 60 referring Dutch hospitals. In total, 230 myasthenic patients including 76 patients with a thymoma (33.0%) were enrolled in this study. Mean follow-up time, procedure time and hospitalization were, respectively 65.7 ± 43.1 months, 111±52.5 min and 3.3 ± 2.2 days. Thymomatous patients had significantly more frequently and more severe complications than nonthymomatous patients (18.4% vs. 3.9%, p<0.001). Follow up data was available in 71.7% of the included patients. The Myasthenia Gravis Foundation of America postintervention score showed any kind of improvement of MG-symptoms after RATS in 82.4% of the patients. Complete stable remission (CSR) or pharmacological remission (PR) of MG was observed in 8.4% and 39.4% of the patients, respectively. Mean time till CSR/PR remission after thymectomy was 26.2 ± 29.2 months. No statistical difference was found in remission or improvement in MGFA scale between thymomatous and nonthymomatous patients. RATS is safe and feasible in patients with MG. The majority of the patients (82.4%) improved after thymectomy. CSR and PR were observed in 8.4% and 39.4% of the patients, respectively, with a mean of 26.2 months after thymectomy. Thymomatous patients had more frequently and more severe complications compared to nonthymomatous patients.

Published
2023

22. Genetic variability in sporadic amyotrophic lateral sclerosis

Author

Neurogenetica, Brain, AIOS Psychiatrie, Neurologen, Neuromuscular Disorders, Translational Neuroscience, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Genetic Risks, Van Daele, Sien Hilde, Moisse, Matthieu, van Vugt, Joke J F A, Zwamborn, Ramona A J, van der Spek, Rick, van Rheenen, Wouter, Van Eijk, Kristel, Kenna, Kevin, Corcia, Philippe, Vourc'h, Patrick, Couratier, Philippe, Hardiman, Orla, McLaughin, Russell, Gotkine, Marc, Drory, Vivian, Ticozzi, Nicola, Silani, Vincenzo, Ratti, Antonia, de Carvalho, Mamede, Mora Pardina, Jesús S, Povedano, Monica, Andersen, Peter M, Weber, Markus, Başak, Nazli A, Shaw, Chris, Shaw, Pamela J, Morrison, Karen E, Landers, John E, Glass, Jonathan D, van Es, Michael, van den Berg, Leonard H, Al-Chalabi, Ammar, Veldink, Jan, Van Damme, Philip, Neurogenetica, Brain, AIOS Psychiatrie, Neurologen, Neuromuscular Disorders, Translational Neuroscience, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Genetic Risks, Van Daele, Sien Hilde, Moisse, Matthieu, van Vugt, Joke J F A, Zwamborn, Ramona A J, van der Spek, Rick, van Rheenen, Wouter, Van Eijk, Kristel, Kenna, Kevin, Corcia, Philippe, Vourc'h, Patrick, Couratier, Philippe, Hardiman, Orla, McLaughin, Russell, Gotkine, Marc, Drory, Vivian, Ticozzi, Nicola, Silani, Vincenzo, Ratti, Antonia, de Carvalho, Mamede, Mora Pardina, Jesús S, Povedano, Monica, Andersen, Peter M, Weber, Markus, Başak, Nazli A, Shaw, Chris, Shaw, Pamela J, Morrison, Karen E, Landers, John E, Glass, Jonathan D, van Es, Michael, van den Berg, Leonard H, Al-Chalabi, Ammar, Veldink, Jan, and Van Damme, Philip

Published
2023

23. Genetic characterization of primary lateral sclerosis

Author

Opleiding Neurologie, Brain, Projectafdeling ALS, Neurologen, Genetic Risks, Regenerative Medicine and Stem Cells, Neuromuscular Disorders, de Boer, Eva M.J., de Vries, Balint S., Pennings, Maartje, Kamsteeg, Erik Jan, Veldink, Jan H., van den Berg, Leonard H., van Es, Michael A., Opleiding Neurologie, Brain, Projectafdeling ALS, Neurologen, Genetic Risks, Regenerative Medicine and Stem Cells, Neuromuscular Disorders, de Boer, Eva M.J., de Vries, Balint S., Pennings, Maartje, Kamsteeg, Erik Jan, Veldink, Jan H., van den Berg, Leonard H., and van Es, Michael A.

Published
2023

24. Association Between Serum Lipids and Survival in Patients With Amyotrophic Lateral Sclerosis: A Meta-analysis and Population-Based Study

Author

Opleiding Neurologie, Neurologen, Brain, Neuromuscular Disorders, Genetic Risks, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Datamanagement Team 1, Janse Van Mantgem, Mark R., Van Rheenen, Wouter, Hackeng, Anemone V., Van Es, Michael A., Veldink, Jan H., Van Den Berg, Leonard H., Van Eijk, Ruben P.A., Opleiding Neurologie, Neurologen, Brain, Neuromuscular Disorders, Genetic Risks, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Datamanagement Team 1, Janse Van Mantgem, Mark R., Van Rheenen, Wouter, Hackeng, Anemone V., Van Es, Michael A., Veldink, Jan H., Van Den Berg, Leonard H., and Van Eijk, Ruben P.A.

Published
2023

25. Outcomes after robotic thymectomy in nonthymomatous versus thymomatous patients with acetylcholine-receptor-antibody-associated myasthenia gravis

Author

Neurologen, Brain, Neuromuscular Disorders, Marcuse, Florit, Hoeijmakers, Janneke G.J., Hochstenbag, Monique, Hamid, Myrurgia Abdul, Keijzers, Marlies, Mané-Damas, Marina, Martinez-Martinez, Pilar, Verschuuren, Jan, Kuks, Jan, Beekman, Roy, van der Kooi, Anneke J., van Doorn, Pieter, van Es, Michael, Maessen, Jos J.G., De Baets, Marc H.V., Neurologen, Brain, Neuromuscular Disorders, Marcuse, Florit, Hoeijmakers, Janneke G.J., Hochstenbag, Monique, Hamid, Myrurgia Abdul, Keijzers, Marlies, Mané-Damas, Marina, Martinez-Martinez, Pilar, Verschuuren, Jan, Kuks, Jan, Beekman, Roy, van der Kooi, Anneke J., van Doorn, Pieter, van Es, Michael, Maessen, Jos J.G., and De Baets, Marc H.V.

Published
2023

26. Development of a Rasch-Built Amyotrophic Lateral Sclerosis Impairment Multidomain Scale to Measure Disease Progression in ALS

Author

Projectafdeling ALS, Brain, Neurologen, Revalidatiegeneeskunde Onderzoek, Child Health, Neuromuscular Disorders, RF&S Revalidatie, Fysiotherapie & Sport, Revalidatie Medisch Volwassenen, Circulatory Health, Genetic Risks, Regenerative Medicine and Stem Cells, de Jongh, Adriaan D, van Eijk, Ruben P A, Bakker, Leonhard A, Bunte, Tommy M, Beelen, Anita, van der Meijden, Conny, van Es, Michael A, Visser-Meily, Johanna, Kruitwagen, Esther T, Veldink, Jan H, van den Berg, Leonard H, Projectafdeling ALS, Brain, Neurologen, Revalidatiegeneeskunde Onderzoek, Child Health, Neuromuscular Disorders, RF&S Revalidatie, Fysiotherapie & Sport, Revalidatie Medisch Volwassenen, Circulatory Health, Genetic Risks, Regenerative Medicine and Stem Cells, de Jongh, Adriaan D, van Eijk, Ruben P A, Bakker, Leonhard A, Bunte, Tommy M, Beelen, Anita, van der Meijden, Conny, van Es, Michael A, Visser-Meily, Johanna, Kruitwagen, Esther T, Veldink, Jan H, and van den Berg, Leonard H

Published
2023

27. Longitudinal Effects of Asymptomatic C9orf72 Carriership on Brain Morphology

Author

Opleiding Neurologie, Projectafdeling ALS, RF&S Team 1 Medisch, Neurologen, Brain, Neuromuscular Disorders, Revalidatiegeneeskunde Onderzoek, Genetic Risks, Regenerative Medicine and Stem Cells, van Veenhuijzen, Kevin, Westeneng, Henk Jan, Tan, Harold H.G., Nitert, Abram D., van der Burgh, Hannelore K., Gosselt, Isabel, van Es, Michael A., Nijboer, Tanja C.W., Veldink, Jan H., van den Berg, Leonard H., Opleiding Neurologie, Projectafdeling ALS, RF&S Team 1 Medisch, Neurologen, Brain, Neuromuscular Disorders, Revalidatiegeneeskunde Onderzoek, Genetic Risks, Regenerative Medicine and Stem Cells, van Veenhuijzen, Kevin, Westeneng, Henk Jan, Tan, Harold H.G., Nitert, Abram D., van der Burgh, Hannelore K., Gosselt, Isabel, van Es, Michael A., Nijboer, Tanja C.W., Veldink, Jan H., and van den Berg, Leonard H.

Published
2023

28. Whole genome sequencing analysis reveals post-zygotic mutation variability in monozygotic twins discordant for amyotrophic lateral sclerosis

Author

Neurogenetica, Brain, Neurologen, Neuromuscular Disorders, Genetica, Genetica Sectie Genoomdiagnostiek, Circulatory Health, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Genetic Risks, Tazelaar, Gijs H.P., Hop, Paul J., Seelen, Meinie, van Vugt, Joke J.F.A., van Rheenen, Wouter, Kool, Lindy, van Eijk, Kristel R., Gijzen, Marleen, Dooijes, Dennis, Moisse, Matthieu, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Nordin, Angelica, Pardina, Jesus S.Mora, Ravits, John, Al-Chalabi, Ammar, Chio, Adriano, McLaughlin, Russell L., Hardiman, Orla, Van Damme, Philip, de Carvalho, Mamede, Neuwirth, Christoph, Weber, Markus, Andersen, Peter M., van den Berg, Leonard H., Veldink, Jan H., van Es, Michael A., Neurogenetica, Brain, Neurologen, Neuromuscular Disorders, Genetica, Genetica Sectie Genoomdiagnostiek, Circulatory Health, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Genetic Risks, Tazelaar, Gijs H.P., Hop, Paul J., Seelen, Meinie, van Vugt, Joke J.F.A., van Rheenen, Wouter, Kool, Lindy, van Eijk, Kristel R., Gijzen, Marleen, Dooijes, Dennis, Moisse, Matthieu, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Nordin, Angelica, Pardina, Jesus S.Mora, Ravits, John, Al-Chalabi, Ammar, Chio, Adriano, McLaughlin, Russell L., Hardiman, Orla, Van Damme, Philip, de Carvalho, Mamede, Neuwirth, Christoph, Weber, Markus, Andersen, Peter M., van den Berg, Leonard H., Veldink, Jan H., and van Es, Michael A.

Published
2023

29. UNC13A in amyotrophic lateral sclerosis: From genetic association to therapeutic target

Author

Opleiding Neurologie, Datamanagement Team 1, Projectafdeling ALS, Brain, Translational Neuroscience, Regenerative Medicine and Stem Cells, Neurologen, Neuromuscular Disorders, Genetic Risks, Willemse, Sean W., Harley, Peter, Van Eijk, Ruben P.A., Demaegd, Koen C., Zelina, Pavol, Pasterkamp, R. Jeroen, Van Damme, Philip, Ingre, Caroline, Van Rheenen, Wouter, Veldink, Jan H., Kiernan, Matthew C., Al-Chalabi, Ammar, Van Den Berg, Leonard H., Fratta, Pietro, Van Es, Michael A., Opleiding Neurologie, Datamanagement Team 1, Projectafdeling ALS, Brain, Translational Neuroscience, Regenerative Medicine and Stem Cells, Neurologen, Neuromuscular Disorders, Genetic Risks, Willemse, Sean W., Harley, Peter, Van Eijk, Ruben P.A., Demaegd, Koen C., Zelina, Pavol, Pasterkamp, R. Jeroen, Van Damme, Philip, Ingre, Caroline, Van Rheenen, Wouter, Veldink, Jan H., Kiernan, Matthew C., Al-Chalabi, Ammar, Van Den Berg, Leonard H., Fratta, Pietro, and Van Es, Michael A.

Published
2023

30. Genetic variability in sporadic amyotrophic lateral sclerosis

Author

Van Daele, Sien Hilde, primary, Moisse, Matthieu, additional, van Vugt, Joke J F A, additional, Zwamborn, Ramona A J, additional, van der Spek, Rick, additional, van Rheenen, Wouter, additional, Van Eijk, Kristel, additional, Kenna, Kevin, additional, Corcia, Philippe, additional, Vourc'h, Patrick, additional, Couratier, Philippe, additional, Hardiman, Orla, additional, McLaughin, Russell, additional, Gotkine, Marc, additional, Drory, Vivian, additional, Ticozzi, Nicola, additional, Silani, Vincenzo, additional, Ratti, Antonia, additional, de Carvalho, Mamede, additional, Mora Pardina, Jesús S, additional, Povedano, Monica, additional, Andersen, Peter M, additional, Weber, Markus, additional, Başak, Nazli A, additional, Shaw, Chris, additional, Shaw, Pamela J, additional, Morrison, Karen E, additional, Landers, John E, additional, Glass, Jonathan D, additional, van Es, Michael, additional, van den Berg, Leonard H, additional, Al-Chalabi, Ammar, additional, Veldink, Jan, additional, and Van Damme, Philip, additional

Published
2023
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31. Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data

Author

Al Khleifat, Ahmad, primary, Iacoangeli, Alfredo, additional, Jones, Ashley R., additional, van Vugt, Joke J. F. A., additional, Moisse, Matthieu, additional, Shatunov, Aleksey, additional, Zwamborn, Ramona A. J., additional, van der Spek, Rick A. A., additional, Cooper-Knock, Johnathan, additional, Topp, Simon, additional, van Rheenen, Wouter, additional, Kenna, Brendan, additional, Van Eijk, Kristel R., additional, Kenna, Kevin, additional, Byrne, Ross, additional, López, Victoria, additional, Opie-Martin, Sarah, additional, Vural, Atay, additional, Campos, Yolanda, additional, Weber, Markus, additional, Smith, Bradley, additional, Fogh, Isabella, additional, Silani, Vincenzo, additional, Morrison, Karen E., additional, Dobson, Richard, additional, van Es, Michael A., additional, McLaughlin, Russell L., additional, Vourc’h, Patrick, additional, Chio, Adriano, additional, Corcia, Philippe, additional, de Carvalho, Mamede, additional, Gotkine, Marc, additional, Panades, Monica Povedano, additional, Mora, Jesus S., additional, Shaw, Pamela J., additional, Landers, John E., additional, Glass, Jonathan D., additional, Shaw, Christopher E., additional, Basak, Nazli, additional, Hardiman, Orla, additional, Robberecht, Wim, additional, Van Damme, Philip, additional, van den Berg, Leonard H., additional, Veldink, Jan H., additional, and Al-Chalabi, Ammar, additional

Published
2022
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33. Facial Onset Sensory and Motor Neuronopathy

Author

de Boer, Eva M.J., Barritt, Andrew W., Elamin, Marwa, Anderson, Stuart J., Broad, Rebecca, Nisbet, Angus, Goedee, H. Stephan, Vázquez Costa, Juan F., Prudlo, Johannes, Vedeler, Christian A., Fernandez, Julio Pardo, Panades, Mónica Povedano, Albertí Aguilo, Maria A., Bella, Eleonora Dalla, Lauria, Giuseppe, Pinto, Wladimir B.V.R., de Souza, Paulo V.S., Oliveira, Acary S.B., Toro, Camilo, van Iersel, Joost, Parson, Malu, Harschnitz, Oliver, van den Berg, Leonard H., Veldink, Jan H., Al-Chalabi, Ammar, Leigh, Peter N., and van Es, Michael A.

Subjects
Malalties autoimmunitàries, Autoimmune diseases, Malalties neurodegeneratives, Neurodegenerative diseases, mental disorders, Review, Malalties rares, Rare diseases
Abstract

Purpose of review: To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN). Recent findings: We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases. Summary: FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis-FTD spectrum.

Published
2021

34. 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
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35. Reduced Expression of the Kinesin-Associated Protein 3 (KIFAP3) Gene Increases Survival in Sporadic Amyotrophic Lateral Sclerosis

Author

Landers, John E., Melki, Judith, Meininger, Vincent, Glass, Jonathan D., van den Berg, Leonard H., van Es, Michael A., Sapp, Peter C., van Vught, Paul W. J., McKenna-Yasek, Diane M., Blauw, Hylke M., Cho, Ting-Jan, Polak, Meraida, Shi, Lijia, Wills, Anne-Marie, Broom, Wendy J., Ticozzi, Nicola, Silani, Vincenzo, Ozoguz, Aslihan, Rodriguez-Leyva, Ildefonso, Veldink, Jan H., Ivinson, Adrian J., Saris, Christiaan G. J., Hosier, Betsy A., Bames-Nessa, Alayna, Couture, Nicole, Wokke, John H. J., Kwiatkowski,, Thomas J., Ophoff, Roel A., Cronin, Simon, Hardiman, Orla, Diekstra, Frank P., Leigh, P. Nigel, Shaw, Christopher E., Simpson, Claire L., Hansen, Valerie K., Powell, John F., Corcia, Philippe, Salachas, François, Heath, Simon, Galan, Pilar, Georges, Franck, Horvitz, H. Robert, Lathrop, Mark, Purcell, Shaun, Al-Chalabi, Ammar, Brown,, Robert H., and Housman, David E.

Published
2009
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36. Author Correction : Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Author

van Rheenen, Wouter, van der Spek, Rick A. A., Bakker, Mark K., van Vugt, Joke J. F. A., Hop, Paul J., Zwamborn, Ramona A. J., de Klein, Niek, Westra, Harm-Jan, Bakker, Olivier B., Deelen, Patrick, Shireby, Gemma, Hannon, Eilis, Moisse, Matthieu, Baird, Denis, Restuadi, Restuadi, Dolzhenko, Egor, Dekker, Annelot M., Gawor, Klara, Westeneng, Henk-Jan, Tazelaar, Gijs H. P., van Eijk, Kristel R., Kooyman, Maarten, Byrne, Ross P., Doherty, Mark, Heverin, Mark, Al Khleifat, Ahmad, Iacoangeli, Alfredo, Shatunov, Aleksey, Ticozzi, Nicola, Cooper-Knock, Johnathan, Smith, Bradley N., Gromicho, Marta, Chandran, Siddharthan, Pal, Suvankar, Morrison, Karen E., Shaw, Pamela J., Hardy, John, Orrell, Richard W., Sendtner, Michael, Meyer, Thomas, Başak, Nazli, van der Kooi, Anneke J., Ratti, Antonia, Fogh, Isabella, Gellera, Cinzia, Lauria, Giuseppe, Corti, Stefania, Cereda, Cristina, Sproviero, Daisy, D'Alfonso, Sandra, Sorarù, Gianni, Siciliano, Gabriele, Filosto, Massimiliano, Padovani, Alessandro, Chiò, Adriano, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Grassano, Maurizio, Beghi, Ettore, Pupillo, Elisabetta, Logroscino, Giancarlo, Nefussy, Beatrice, Osmanovic, Alma, Nordin, Angelica, Lerner, Yossef, Zabari, Michal, Gotkine, Marc, Baloh, Robert H., Bell, Shaughn, Vourc'h, Patrick, Corcia, Philippe, Couratier, Philippe, Millecamps, Stéphanie, Meininger, Vincent, Salachas, François, Mora Pardina, Jesus S., Assialioui, Abdelilah, Rojas-Garcia, Ricard, Dion, Patrick A., Ross, Jay P., Ludolph, Albert C., Weishaupt, Jochen H., Brenner, David, Freischmidt, Axel, Bensimon, Gilbert, Brice, Alexis, Durr, Alexandra, Payan, Christine A. M., Saker-Delye, Safa, Wood, Nicholas W., Topp, Simon, Rademakers, Rosa, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Ripke, Stephan, Braun, Alice, Kraft, Julia, Whiteman, David C., Olsen, Catherine M., Uitterlinden, André G, Hofman, Albert, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M., Amouyel, Philippe, Traynor, Bryan J., Singleton, Andrew B., Mitne Neto, Miguel, Cauchi, Ruben J., Ophoff, Roel A., Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, van Deerlin, Vivianna M., Grosskreutz, Julian, Roediger, Annekathrin, Gaur, Nayana, Jörk, Alexander, Barthel, Tabea, Theele, Erik, Ilse, Benjamin, Stubendorff, Beatrice, Witte, Otto W., Steinbach, Robert, Hübner, Christian A., Graff, Caroline, Brylev, Lev, Fominykh, Vera, Demeshonok, Vera, Ataulina, Anastasia, Rogelj, Boris, Koritnik, Blaž, Zidar, Janez, Ravnik-Glavač, Metka, Glavač, Damjan, Stević, Zorica, Drory, Vivian, Povedano, Monica, Blair, Ian P., Kiernan, Matthew C., Benyamin, Beben, Henderson, Robert D., Furlong, Sarah, Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth A., Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Mather, Karen A., Sachdev, Perminder S., Henders, Anjali K., Wallace, Leanne, De Carvalho, Mamede, Pinto, Susana, Petri, Susanne, Weber, Markus, Rouleau, Guy A., Silani, Vincenzo, Curtis, Charles J., Breen, Gerome, Glass, Jonathan D., Brown, Robert H., Landers, John E., Shaw, Christopher E., Andersen, Peter Munch, Groen, Ewout J. N., van Es, Michael A., Pasterkamp, R. Jeroen, Fan, Dongsheng, Garton, Fleur C., McRae, Allan F., Smith, George Davey, Gaunt, Tom R., Eberle, Michael A., Mill, Jonathan, McLaughlin, Russell L., Hardiman, Orla, Kenna, Kevin P., Wray, Naomi R., Tsai, Ellen, Runz, Heiko, Franke, Lude, Al-Chalabi, Ammar, Van Damme, Philip, van den Berg, Leonard H., Veldink, Jan H., Universitat Autònoma de Barcelona, van Rheenen, Wouter, van der Spek, Rick A. A., Bakker, Mark K., van Vugt, Joke J. F. A., Hop, Paul J., Zwamborn, Ramona A. J., de Klein, Niek, Westra, Harm-Jan, Bakker, Olivier B., Deelen, Patrick, Shireby, Gemma, Hannon, Eilis, Moisse, Matthieu, Baird, Denis, Restuadi, Restuadi, Dolzhenko, Egor, Dekker, Annelot M., Gawor, Klara, Westeneng, Henk-Jan, Tazelaar, Gijs H. P., van Eijk, Kristel R., Kooyman, Maarten, Byrne, Ross P., Doherty, Mark, Heverin, Mark, Al Khleifat, Ahmad, Iacoangeli, Alfredo, Shatunov, Aleksey, Ticozzi, Nicola, Cooper-Knock, Johnathan, Smith, Bradley N., Gromicho, Marta, Chandran, Siddharthan, Pal, Suvankar, Morrison, Karen E., Shaw, Pamela J., Hardy, John, Orrell, Richard W., Sendtner, Michael, Meyer, Thomas, Başak, Nazli, van der Kooi, Anneke J., Ratti, Antonia, Fogh, Isabella, Gellera, Cinzia, Lauria, Giuseppe, Corti, Stefania, Cereda, Cristina, Sproviero, Daisy, D'Alfonso, Sandra, Sorarù, Gianni, Siciliano, Gabriele, Filosto, Massimiliano, Padovani, Alessandro, Chiò, Adriano, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Grassano, Maurizio, Beghi, Ettore, Pupillo, Elisabetta, Logroscino, Giancarlo, Nefussy, Beatrice, Osmanovic, Alma, Nordin, Angelica, Lerner, Yossef, Zabari, Michal, Gotkine, Marc, Baloh, Robert H., Bell, Shaughn, Vourc'h, Patrick, Corcia, Philippe, Couratier, Philippe, Millecamps, Stéphanie, Meininger, Vincent, Salachas, François, Mora Pardina, Jesus S., Assialioui, Abdelilah, Rojas-Garcia, Ricard, Dion, Patrick A., Ross, Jay P., Ludolph, Albert C., Weishaupt, Jochen H., Brenner, David, Freischmidt, Axel, Bensimon, Gilbert, Brice, Alexis, Durr, Alexandra, Payan, Christine A. M., Saker-Delye, Safa, Wood, Nicholas W., Topp, Simon, Rademakers, Rosa, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Ripke, Stephan, Braun, Alice, Kraft, Julia, Whiteman, David C., Olsen, Catherine M., Uitterlinden, André G, Hofman, Albert, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M., Amouyel, Philippe, Traynor, Bryan J., Singleton, Andrew B., Mitne Neto, Miguel, Cauchi, Ruben J., Ophoff, Roel A., Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, van Deerlin, Vivianna M., Grosskreutz, Julian, Roediger, Annekathrin, Gaur, Nayana, Jörk, Alexander, Barthel, Tabea, Theele, Erik, Ilse, Benjamin, Stubendorff, Beatrice, Witte, Otto W., Steinbach, Robert, Hübner, Christian A., Graff, Caroline, Brylev, Lev, Fominykh, Vera, Demeshonok, Vera, Ataulina, Anastasia, Rogelj, Boris, Koritnik, Blaž, Zidar, Janez, Ravnik-Glavač, Metka, Glavač, Damjan, Stević, Zorica, Drory, Vivian, Povedano, Monica, Blair, Ian P., Kiernan, Matthew C., Benyamin, Beben, Henderson, Robert D., Furlong, Sarah, Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth A., Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Mather, Karen A., Sachdev, Perminder S., Henders, Anjali K., Wallace, Leanne, De Carvalho, Mamede, Pinto, Susana, Petri, Susanne, Weber, Markus, Rouleau, Guy A., Silani, Vincenzo, Curtis, Charles J., Breen, Gerome, Glass, Jonathan D., Brown, Robert H., Landers, John E., Shaw, Christopher E., Andersen, Peter Munch, Groen, Ewout J. N., van Es, Michael A., Pasterkamp, R. Jeroen, Fan, Dongsheng, Garton, Fleur C., McRae, Allan F., Smith, George Davey, Gaunt, Tom R., Eberle, Michael A., Mill, Jonathan, McLaughlin, Russell L., Hardiman, Orla, Kenna, Kevin P., Wray, Naomi R., Tsai, Ellen, Runz, Heiko, Franke, Lude, Al-Chalabi, Ammar, Van Damme, Philip, van den Berg, Leonard H., Veldink, Jan H., and Universitat Autònoma de Barcelona

Published
2022

37. Clinical trials in pediatric ALS: a TRICALS feasibility study

Author

Kliest, Tessa, Van Eijk, Ruben P.A., Al-Chalabi, Ammar, Albanese, Alberto, Andersen, Peter M., Amador, Maria Del Mar, Bråthen, Geir, Brunaud-Danel, Veronique, Brylev, Lev, Camu, William, De Carvalho, Mamede, Cereda, Cristina, Cetin, Hakan, Chaverri, Delia, Chiò, Adriano, Corcia, Philippe, Couratier, Philippe, De Marchi, Fabiola, Desnuelle, Claude, Van Es, Michael A., Esteban, JesÚs, Filosto, Massimiliano, GarcÍa Redondo, Alberto, Grosskreutz, Julian, Hanemann, Clemens O., Holmøy, Trygve, Høyer, Helle, Ingre, Caroline, Koritnik, Blaz, Kuzma-Kozakiewicz, Magdalena, Lambert, Thomas, Leigh, Peter N., Lunetta, Christian, Mandrioli, Jessica, Mcdermott, Christopher J., Meyer, Thomas, Mora, Jesus S., Petri, Susanne, Povedano, Mónica, Reviers, Evy, Riva, Nilo, Roes, Kit C.B., Rubio, Miguel Á., Salachas, François, Sarafov, Stayko, Sorarù, Gianni, Stevic, Zorica, Svenstrup, Kirsten, Møller, Anette Torvin, Turner, Martin R., Van Damme, Philip, Van Leeuwen, Lucie A.G., Varona, Luis, VÁzquez Costa, Juan F., Weber, Markus, Hardiman, Orla, Van Den Berg, Leonard H., Kliest, Tessa, Van Eijk, Ruben P.A., Al-Chalabi, Ammar, Albanese, Alberto, Andersen, Peter M., Amador, Maria Del Mar, Bråthen, Geir, Brunaud-Danel, Veronique, Brylev, Lev, Camu, William, De Carvalho, Mamede, Cereda, Cristina, Cetin, Hakan, Chaverri, Delia, Chiò, Adriano, Corcia, Philippe, Couratier, Philippe, De Marchi, Fabiola, Desnuelle, Claude, Van Es, Michael A., Esteban, JesÚs, Filosto, Massimiliano, GarcÍa Redondo, Alberto, Grosskreutz, Julian, Hanemann, Clemens O., Holmøy, Trygve, Høyer, Helle, Ingre, Caroline, Koritnik, Blaz, Kuzma-Kozakiewicz, Magdalena, Lambert, Thomas, Leigh, Peter N., Lunetta, Christian, Mandrioli, Jessica, Mcdermott, Christopher J., Meyer, Thomas, Mora, Jesus S., Petri, Susanne, Povedano, Mónica, Reviers, Evy, Riva, Nilo, Roes, Kit C.B., Rubio, Miguel Á., Salachas, François, Sarafov, Stayko, Sorarù, Gianni, Stevic, Zorica, Svenstrup, Kirsten, Møller, Anette Torvin, Turner, Martin R., Van Damme, Philip, Van Leeuwen, Lucie A.G., Varona, Luis, VÁzquez Costa, Juan F., Weber, Markus, Hardiman, Orla, and Van Den Berg, Leonard H.

Abstract

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA). Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe. Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS. Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS. Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.

Published
2022
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38. Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data

Author

Vural, Atay (ORCID 0000-0003-3222-874X & YÖK ID 182369); Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512); Weber, Markus, Al Khleifat, Ahmad; Iacoangeli, Alfredo; Jones, Ashley R.; van Vugt, Joke J. F. A.; Moisse, Matthieu; Shatunov, Aleksey; Zwamborn, Ramona A. J.; van der Spek, Rick A. A.; Cooper-Knock, Johnathan; Topp, Simon; van Rheenen, Wouter; Kenna, Brendan; Van Eijk, Kristel R.; Kenna, Kevin; Byrne, Ross; Lopez, Victoria; Opie-Martin, Sarah; Campos, Yolanda; Smith, Bradley; Fogh, Isabella; Silani, Vincenzo; Morrison, Karen E.; Dobson, Richard; van Es, Michael A.; McLaughlin, Russell L.; Vourc'h, Patrick; Chio, Adriano; Corcia, Philippe; de Carvalho, Mamede; Gotkine, Marc; Panades, Monica Povedano; Mora, Jesus S.; Shaw, Pamela J.; Landers, John E.; Glass, Jonathan D.; Shaw, Christopher E.; Hardiman, Orla; Robberecht, Wim; Van Damme, Philip; van den Berg, Leonard H.; Veldink, Jan H.; Al-Chalabi, Ammar; the Project MinE Consortium, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Vural, Atay (ORCID 0000-0003-3222-874X & YÖK ID 182369); Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512); Weber, Markus, Al Khleifat, Ahmad; Iacoangeli, Alfredo; Jones, Ashley R.; van Vugt, Joke J. F. A.; Moisse, Matthieu; Shatunov, Aleksey; Zwamborn, Ramona A. J.; van der Spek, Rick A. A.; Cooper-Knock, Johnathan; Topp, Simon; van Rheenen, Wouter; Kenna, Brendan; Van Eijk, Kristel R.; Kenna, Kevin; Byrne, Ross; Lopez, Victoria; Opie-Martin, Sarah; Campos, Yolanda; Smith, Bradley; Fogh, Isabella; Silani, Vincenzo; Morrison, Karen E.; Dobson, Richard; van Es, Michael A.; McLaughlin, Russell L.; Vourc'h, Patrick; Chio, Adriano; Corcia, Philippe; de Carvalho, Mamede; Gotkine, Marc; Panades, Monica Povedano; Mora, Jesus S.; Shaw, Pamela J.; Landers, John E.; Glass, Jonathan D.; Shaw, Christopher E.; Hardiman, Orla; Robberecht, Wim; Van Damme, Philip; van den Berg, Leonard H.; Veldink, Jan H.; Al-Chalabi, Ammar; the Project MinE Consortium, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine

Abstract

Background: amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive weakness of voluntary muscles, with death following from neuromuscular respiratory failure, typically within 3 to 5 years. There is a strong genetic contribution to ALS risk. In 10% or more, a family history of ALS or frontotemporal dementia is obtained, and the Mendelian genes responsible for ALS in such families have now been identified in about 50% of cases. Only about 14% of apparently sporadic ALS is explained by known genetic variation, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication, differ between sexes, and shorten naturally with age. Sex and age are risk factors for ALS and we therefore investigated telomere length in ALS. Methods: samples were from Project MinE, an international ALS whole genome sequencing consortium that includes phenotype data. For validation we used donated brain samples from motor cortex from people with ALS and controls. Ancestry and relatedness were evaluated by principal components analysis and relationship matrices of DNA microarray data. Whole genome sequence data were from Illumina HiSeq platforms and aligned using the Isaac pipeline. TelSeq was used to quantify telomere length using whole genome sequence data. We tested the association of telomere length with ALS and ALS survival using Cox regression. Results: there were 6,580 whole genome sequences, reducing to 6,195 samples (4,315 from people with ALS and 1,880 controls) after quality control, and 159 brain samples (106 ALS, 53 controls). Accounting for age and sex, there was a 20% (95% CI 14%, 25%) increase of telomere length in people with ALS compared to controls (p = 1.1 × 10?12), validated in the brain samples (p = 0.03). Those with shorter telomeres had a 10% increase in median survival (p = 5.0×10?7). Although there was no difference, European Community's Health Seventh Framework Program (FP7/2007-2013); European Union (EU); Horizon 2020; H2020-PHC2014-two-stage; European Research Council (ERC); Research and Innovation Programme; AAK was funded by ALS Association Milton Safenowitz Research Fellowship (grant number 22-PDF-609. doi: 10.52546/pc.gr.150909), The Motor Neurone Disease Association (MNDA) Fellowship (Al Khleifat/Oct21/975799), The Darby Rimmer Foundation, and The NIHRMaudsley Biomedical Research Centre. This project was also funded by the MND Association and the Wellcome Trust. 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 and MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)]. AA-C was a NIHR Senior Investigator. CS and AA-C received salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King's College London. The collaboration project was co-funded by the PPP Allowance made available by Health ~Holland, Top Sector Life Sciences and Health, to stimulate public-private partnerships. Project MinE Belgium was supported by a grant from IWT, the Belgian ALS Liga and a grant from Opening the Future Fund (KU Leuven). PVD holds a senior clinical investigatorship of FWO-Vlaanderen and was supported by E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga Belgie and the KU Leuven funds ""Een Hart voor ALS,"" ""Laeversfonds voor ALS Onderzoek,"" and the ""Valery Perrier Race against ALS Fund"". RM was supported by Science Foundation Ireland (17/CDA/4737). MinE USA was funded by the US ALS Association.

Published
2022

39. Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial

Author

UMC Utrecht Academie, Opleiding Neurologie, Biostatistiek Onderzoek, Genetica, Genetica Sectie Genoomdiagnostiek, Brain, Projectafdeling ALS, Neurologen, Regenerative Medicine and Stem Cells, Neuromuscular Disorders, Datamanagement Team 1, Willemse, Sean W., Roes, Kit C.B., Van Damme, Philip, Hardiman, Orla, Ingre, Caroline, Povedano, Monica, Wray, Naomi R., Gijzen, Marleen, de Pagter, Mirjam S., Demaegd, Koen C., Janse, Annemarie F.C., Vink, Roel G., Sleutjes, Boudewijn T.H.M., Chiò, Adriano, Corcia, Philippe, Reviers, Evy, Al-Chalabi, Ammar, Kiernan, Matthew C., van den Berg, Leonard H., van Es, Michael A., van Eijk, Ruben P.A., UMC Utrecht Academie, Opleiding Neurologie, Biostatistiek Onderzoek, Genetica, Genetica Sectie Genoomdiagnostiek, Brain, Projectafdeling ALS, Neurologen, Regenerative Medicine and Stem Cells, Neuromuscular Disorders, Datamanagement Team 1, Willemse, Sean W., Roes, Kit C.B., Van Damme, Philip, Hardiman, Orla, Ingre, Caroline, Povedano, Monica, Wray, Naomi R., Gijzen, Marleen, de Pagter, Mirjam S., Demaegd, Koen C., Janse, Annemarie F.C., Vink, Roel G., Sleutjes, Boudewijn T.H.M., Chiò, Adriano, Corcia, Philippe, Reviers, Evy, Al-Chalabi, Ammar, Kiernan, Matthew C., van den Berg, Leonard H., van Es, Michael A., and van Eijk, Ruben P.A.

Published
2022

40. Rhabdomyolysis after COVID-19 Comirnaty Vaccination: A Case Report

Author

MS Radiologie, Neurologen, Brain, Neuromuscular Disorders, Ruijters, Veerle J., Van Der Meulen, Marjon F.G., Van Es, Michael A., Smit, Tessa, Hoogendijk, Jessica E., MS Radiologie, Neurologen, Brain, Neuromuscular Disorders, Ruijters, Veerle J., Van Der Meulen, Marjon F.G., Van Es, Michael A., Smit, Tessa, and Hoogendijk, Jessica E.

Published
2022

41. MRI Clustering Reveals Three ALS Subtypes With Unique Neurodegeneration Patterns

Author

Projectafdeling ALS, Opleiding Neurologie, Brain, Neuropsychologie, Neurologen, Genetic Risks, Regenerative Medicine and Stem Cells, Tan, Harold H G, Westeneng, Henk-Jan, Nitert, Abram D, van Veenhuijzen, Kevin, Meier, Jil M, van der Burgh, Hannelore K, van Zandvoort, Martine J E, van Es, Michael A, Veldink, Jan H, van den Berg, Leonard H, Projectafdeling ALS, Opleiding Neurologie, Brain, Neuropsychologie, Neurologen, Genetic Risks, Regenerative Medicine and Stem Cells, Tan, Harold H G, Westeneng, Henk-Jan, Nitert, Abram D, van Veenhuijzen, Kevin, Meier, Jil M, van der Burgh, Hannelore K, van Zandvoort, Martine J E, van Es, Michael A, Veldink, Jan H, and van den Berg, Leonard H

Published
2022

42. Characterising ALS disease progression according to El Escorial and Gold Coast criteria

Author

Neurologen, Brain, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Genetic Risks, Neuromuscular Disorders, de Jongh, Adriaan D, Braun, Nathalie, Weber, Markus, van Es, Michael A, Masrori, Pegah, Veldink, Jan H, van Damme, Philip, van den Berg, Leonard H, van Eijk, Ruben P A, Neurologen, Brain, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Genetic Risks, Neuromuscular Disorders, de Jongh, Adriaan D, Braun, Nathalie, Weber, Markus, van Es, Michael A, Masrori, Pegah, Veldink, Jan H, van Damme, Philip, van den Berg, Leonard H, and van Eijk, Ruben P A

Published
2022

43. Distal spinal muscular atrophy featured by predominant calf muscle involvement in VRK1 associated disease - Case series and review

Author

Opleiding Neurologie, Genetica Klinische Genetica, Brain, Neurologen, Child Health, Genetica Sectie Genoomdiagnostiek, Pathologie Pathologen staf, Cancer, Neuromuscular Disorders, Demaegd, Koen, Brilstra, Eva H, Hoogendijk, Jessica E, de Bie, Charlotte I, de Pagter, Mirjam S, van Hecke, Wim, Mühlebner, Angelika, van Es, Michael A, Milone, Margherita, van Rheenen, Wouter, Opleiding Neurologie, Genetica Klinische Genetica, Brain, Neurologen, Child Health, Genetica Sectie Genoomdiagnostiek, Pathologie Pathologen staf, Cancer, Neuromuscular Disorders, Demaegd, Koen, Brilstra, Eva H, Hoogendijk, Jessica E, de Bie, Charlotte I, de Pagter, Mirjam S, van Hecke, Wim, Mühlebner, Angelika, van Es, Michael A, Milone, Margherita, and van Rheenen, Wouter

Published
2022

44. Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

Author

Neurogenetica, AIOS Psychiatrie, Neurologen, Brain, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Genetic Risks, Neuromuscular Disorders, Al Khleifat, Ahmad, Iacoangeli, Alfredo, van Vugt, Joke J F A, Bowles, Harry, Moisse, Matthieu, Zwamborn, Ramona A J, van der Spek, Rick A A, Shatunov, Aleksey, Cooper-Knock, Johnathan, Topp, Simon, Byrne, Ross, Gellera, Cinzia, López, Victoria, Jones, Ashley R, Opie-Martin, Sarah, Vural, Atay, Campos, Yolanda, van Rheenen, Wouter, Kenna, Brendan, Van Eijk, Kristel R, Kenna, Kevin, Weber, Markus, Smith, Bradley, Fogh, Isabella, Silani, Vincenzo, Morrison, Karen E, Dobson, Richard, van Es, Michael A, McLaughlin, Russell L, Vourc'h, Patrick, Chio, Adriano, Corcia, Philippe, de Carvalho, Mamede, Gotkine, Marc, Panades, Monica P, Mora, Jesus S, Shaw, Pamela J, Landers, John E, Glass, Jonathan D, Shaw, Christopher E, Basak, Nazli, Hardiman, Orla, Robberecht, Wim, Van Damme, Philip, van den Berg, Leonard H, Veldink, Jan H, Al-Chalabi, Ammar, Neurogenetica, AIOS Psychiatrie, Neurologen, Brain, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Genetic Risks, Neuromuscular Disorders, Al Khleifat, Ahmad, Iacoangeli, Alfredo, van Vugt, Joke J F A, Bowles, Harry, Moisse, Matthieu, Zwamborn, Ramona A J, van der Spek, Rick A A, Shatunov, Aleksey, Cooper-Knock, Johnathan, Topp, Simon, Byrne, Ross, Gellera, Cinzia, López, Victoria, Jones, Ashley R, Opie-Martin, Sarah, Vural, Atay, Campos, Yolanda, van Rheenen, Wouter, Kenna, Brendan, Van Eijk, Kristel R, Kenna, Kevin, Weber, Markus, Smith, Bradley, Fogh, Isabella, Silani, Vincenzo, Morrison, Karen E, Dobson, Richard, van Es, Michael A, McLaughlin, Russell L, Vourc'h, Patrick, Chio, Adriano, Corcia, Philippe, de Carvalho, Mamede, Gotkine, Marc, Panades, Monica P, Mora, Jesus S, Shaw, Pamela J, Landers, John E, Glass, Jonathan D, Shaw, Christopher E, Basak, Nazli, Hardiman, Orla, Robberecht, Wim, Van Damme, Philip, van den Berg, Leonard H, Veldink, Jan H, and Al-Chalabi, Ammar

Published
2022

45. Cortical and subcortical changes in resting-state neuronal activity and connectivity in early symptomatic ALS and advanced frontotemporal dementia

Author

MS Neonatologie, Neurologen, Brain, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Genetic Risks, Neuromuscular Disorders, Govaarts, Rosanne, Beeldman, Emma, Fraschini, Matteo, Griffa, Alessandra, Engels, Marjolein M A, van Es, Michael A, Veldink, Jan H, van den Berg, Leonard H, van der Kooi, Anneke J, Pijnenburg, Yolande A L, de Visser, Marianne, Stam, Cornelis J, Raaphorst, Joost, Hillebrand, Arjan, MS Neonatologie, Neurologen, Brain, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Genetic Risks, Neuromuscular Disorders, Govaarts, Rosanne, Beeldman, Emma, Fraschini, Matteo, Griffa, Alessandra, Engels, Marjolein M A, van Es, Michael A, Veldink, Jan H, van den Berg, Leonard H, van der Kooi, Anneke J, Pijnenburg, Yolande A L, de Visser, Marianne, Stam, Cornelis J, Raaphorst, Joost, and Hillebrand, Arjan

Published
2022

46. Sensitivity of brain MRI and neurological examination for detection of upper motor neurone degeneration in amyotrophic lateral sclerosis

Author

Projectafdeling ALS, Opleiding Neurologie, Brain, Neurologen, Divisie Beeld, Researchgr. Neuroradiologie, Regenerative Medicine and Stem Cells, Genetic Risks, Neuromuscular Disorders, Nitert, Abram D, Tan, Harold Hg, Walhout, Renée, Knijnenburg, Nienke L, van Es, Michael A, Veldink, Jan H, Hendrikse, Jeroen, Westeneng, Henk-Jan, van den Berg, Leonard H, Projectafdeling ALS, Opleiding Neurologie, Brain, Neurologen, Divisie Beeld, Researchgr. Neuroradiologie, Regenerative Medicine and Stem Cells, Genetic Risks, Neuromuscular Disorders, Nitert, Abram D, Tan, Harold Hg, Walhout, Renée, Knijnenburg, Nienke L, van Es, Michael A, Veldink, Jan H, Hendrikse, Jeroen, Westeneng, Henk-Jan, and van den Berg, Leonard H

Published
2022

47. 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
Traumatic brain injury, Paediatric, Epidemiology, Incidence
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

48. Discussing Personalized Prognosis Empowers Patients with Amyotrophic Lateral Sclerosis to Regain Control over Their Future: A Qualitative Study

Author

van Eenennaam, Remko M., primary, Koppenol, Loulou S., additional, Kruithof, Willeke J., additional, Kruitwagen-van Reenen, Esther T., additional, Pieters, Sotice, additional, van Es, Michael A., additional, van den Berg, Leonard H., additional, Visser-Meily, Johanna M. A., additional, and Beelen, Anita, additional

Published
2021
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49. 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
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50. Incidence, Prevalence and Geographical Clustering of Motor Neuron Disease in the Netherlands

Author

de Jongh, Adriaan D, van Eijk, Ruben P A, Peters, Susan M, van Es, Michael A, Horemans, Anja M C, van der Kooi, Anneke J, Voermans, Nicol C, Vermeulen, Roel C H, Veldink, Jan H, van den Berg, Leonard H, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, IRAS OH Epidemiology Chemical Agents, and dIRAS RA-2

Subjects
0301 basic medicine, Disease, Article, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Risk mapping, Medicine, Poisson regression, Prospective cohort study, business.industry, Mortality rate, Incidence (epidemiology), Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Confidence interval, 030104 developmental biology, symbols, Neurology (clinical), business, 030217 neurology & neurosurgery, Demography, Incidence prevalence
Abstract

ObjectiveTo assess time trends in motor neuron disease (MND) incidence, prevalence, and mortality and to investigate geographic clustering of MND cases in the Netherlands from 1998 to 2017, we analyzed data from the Netherlands Personal Records database, the Netherlands MND Center, and the Netherlands Patient Association of Neuromuscular Diseases.MethodsIn this prospective cohort study, Poisson regression was used to assess time trends in MND risk. We calculated age- and sex-standardized, observed, and expected cases for 1,694 areas. Bayesian smoothed risk mapping was used to investigate geographic MND risk.ResultsWe identified 7,992 MND cases, reflecting an incidence of 2.64 (95% confidence interval [CI] 2.62–2.67) per 100,000 person-years and a prevalence of 9.5 (95% CI 9.1–10.0) per 100,000 persons. Highest age-standardized prevalence and mortality rates occurred at a later age in men than in women (p < 0.001). Unadjusted mortality rates increased by 53.2% from 2.57 per 100,000 person-years in 1998 to 3.86 per 100,000 person-years in 2017. After adjustment for age and sex, an increase in MND mortality rate of 14.1% (95% CI 5.7%–23.2%, p < 0.001) remained. MND relative risk ranged from 0.78 to 1.43 between geographic areas; multiple urban and rural high-risk areas were identified.ConclusionsWe found a significant national increase in MND mortality from 1998 through 2017, explained only partly by an aging Dutch population, and a geographic variability in MND risk, suggesting a role for environmental or demographic risk factors.

Published
2021

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