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Your search keyword '"Rick A.A. van der Spek"' showing total 2 results
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2 results on '"Rick A.A. van der Spek"'

1. 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
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2. CHCHD10 variants in amyotrophic lateral sclerosis: Where is the evidence?

Author

Bas Middelkoop, Rick A.A. van der Spek, Matthieu Moisse, Kevin P. Kenna, Maarten Kooyman, Karen E. Morrison, Orla HardimanMD, Philip Van Damme, Michael A. van Es, Fulya Akçimen, John Landers, Jesus S. Mora, William J. Brands, Jan H. Veldink, Gijs H.P. Tazelaar, Kristel E. van Eijk, William Sproviero, Raymond D. Schellevis, Stephen E. Newhouse, Leonard H. van den Berg, Christopher Shaw, Mònica Povedano, Cemile Kocoglu, Jonathan D. Glass, A. Nazli Basak, Ceren Tunca, Sara L. Pulit, Wouter van Rheenen, Pamela J. Shaw, Ammar Al-Chalabi, Perry T.C. van Doormaal, Wim Robberecht, Annelot M. Dekker, and Russell L. McLaughlin

Subjects
0301 basic medicine, Nonsynonymous substitution, Genetics, Mutation, Mitochondrial disease, Biology, medicine.disease, medicine.disease_cause, Genome, Phenotype, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, medicine, Clinical significance, Neurology (clinical), Amyotrophic lateral sclerosis, medicine.symptom, Myopathy, 030217 neurology & neurosurgery
Abstract

Objective: After the initial report of a CHCHD10 mutation in mitochondrial disease with features resembling amyotrophic lateral sclerosis (ALS), CHCHD10 mutations have been considered to be a frequent cause for ALS. However, the exact pathogenicity and clinical significance of these mutations remain unclear. Here, we aimed to determine the role of CHCHD10 mutations in ALS. Methods: We analyzed 4,365 whole genome sequenced ALS patients and 1,832 controls from 7 different countries and examined all nonsynonymous single nucleotide variants in CHCHD10. These were tested for association with ALS, independently and in aggregate using several genetic burden tests (including sequence kernel association test [SKAT], optimal unified test [SKAT-O], and Firth logistic regression). Results: We identified 3 new variants in cases, but only 1 was ALS-specific. lso, 1 control-specific mutation was identified. There was no increased burden of rare coding mutations among ALS patients compared to controls (p=0.86, p=0.86, and p=0.88 for SKAT, SKAT-O, and Firth, respectively). The few carriers with potential pathogenic CHCHD10 mutations exhibited a slowly progressive ALS-like phenotype with atypical features such as myopathy and deafness. Interpretation: CHCHD10 mutations seem to be a far less prevalent cause of pure ALS than previously suggested, and instead appear related to more complex phenotypes. There appears to be insufficient evidence for the pathogenicity of most previously reported variants in pure ALS. This study shows that routine testing for CHCHD10 mutations in pure ALS is not recommended and illustrates the importance of sufficient genetic and functional evidence in establishing pathogenicity of genetic variants.

Published
2018
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