36 results on '"Van Es, Michael A."'
Search Results
2. Development of a Rasch-Built Amyotrophic Lateral Sclerosis Impairment Multidomain Scale to Measure Disease Progression in ALS.
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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 M. A., Kruitwagen, Esther T., Veldink, Jan H., and van den Berg, Leonard H.
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- 2023
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3. Susceptibility and disease modifier genes in amyotrophic lateral sclerosis: from genetic associations to therapeutic implications
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Willemse, Sean W. and van Es, Michael A.
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- 2023
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4. Association Between Serum Lipids and Survival in Patients With Amyotrophic Lateral Sclerosis: A Meta-analysis and Population-Based Study.
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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.
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- 2023
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5. Association Between Serum Lipids and Survival in Patients With Amyotrophic Lateral Sclerosis
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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.
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- 2023
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6. UNC13Ain amyotrophic lateral sclerosis: from genetic association to therapeutic target
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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
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options and an incompletely understood pathophysiology. Although genomewide association studies (GWAS) have advanced our understanding of the disease, the precise manner in which risk polymorphisms contribute to disease pathogenesis remains unclear. Of relevance, GWAS have shown that a polymorphism (rs12608932) in the UNC13Agene is associated with risk for both ALS and frontotemporal dementia (FTD). Homozygosity for the C-allele at rs12608932 modifies the ALS phenotype, as these patients are more likely to have bulbar-onset disease, cognitive impairment and FTD at baseline as well as shorter survival. UNC13A is expressed in neuronal tissue and is involved in maintaining synaptic active zones, by enabling the priming and docking of synaptic vesicles. In the absence of functional TDP-43, risk variants in UNC13Alead to the inclusion of a cryptic exon in UNC13Amessenger RNA, subsequently leading to nonsense mediated decay, with loss of functional protein. Depletion of UNC13Aleads to impaired neurotransmission. Recent discoveries have identified UNC13Aas a potential target for therapy development in ALS, with a confirmatory trial with lithium carbonate in UNC13Acases now underway and future approaches with antisense oligonucleotides currently under consideration. Considering UNC13Ais a potent phenotypic modifier, it may also impact clinical trial outcomes. This present review describes the path from the initial discovery of UNC13Aas a risk gene in ALS to the current therapeutic options being explored and how knowledge of its distinct phenotype needs to be taken into account in future trials.
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- 2023
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7. Epidemiology of paediatric moderate and severe traumatic brain injury in the Netherlands.
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Jochems, Denise, van Rein, Eveline, Niemeijer, Menco, van Heijl, Mark, van Es, Michael A., Nijboer, Tanja, Leenen, Luke P.H., Houwert, Roderick M., and van Wessem, Karlijn J.P.
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BRAIN injuries ,PEDIATRICS ,CHILD mortality ,AGE groups ,CYCLING accidents - Abstract
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. 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. 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 <5 years, incidence rate was highest in patients ≥16 years. Falls were more common than road traffic accidents (RTA), but RTAs occurred far more frequently amongst children over 10. RTAs predominantly consisted of bicycle accidents. Mortality rates increased from youngest to oldest age groups, as did the chances of a Glasgow Outcome Scale score of 3. Paediatric moderate-severe TBI represents a significant problem in the Netherlands. Falls are the most common mechanism of injury amongst younger children and RTAs amongst older children. Unique for the Netherlands is the vast amount of bicycle accident related injuries. • Traumatic brain injury main cause of death in children globally. • Incidence rate in the Netherlands 14/100,000 person years from January 2015 until December 2017. • 5% of these children died, mortality rates increase with age as did chances of being dependent on others in daily life. • Falls were the most common trauma mechanism, followed by road traffic accidents. • Bicycle accidents were by far the most common amongst road traffic accidents. [ABSTRACT FROM AUTHOR]
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- 2021
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8. Sensitivity of brain MRI and neurological examination for detection of upper motor neurone degeneration in amyotrophic lateral sclerosis
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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
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ObjectivesTo investigate sensitivity of brain MRI and neurological examination for detection of upper motor neuron (UMN) degeneration in patients with amyotrophic lateral sclerosis (ALS).MethodsWe studied 192 patients with ALS and 314 controls longitudinally. All patients visited our centre twice and underwent full neurological examination and brain MRI. At each visit, we assessed UMN degeneration by measuring motor cortex thickness (CT) and pyramidal tract fibre density (FD) corresponding to five body regions (bulbar region and limbs). For each body region, we measured degree of clinical UMN and lower motor neuron (LMN) symptom burden using a validated scoring system.ResultsWe found deterioration over time of CT of motor regions (p≤0.0081) and progression of UMN signs of bulbar region and left arm (p≤0.04). FD was discriminative between controls and patients with moderate/severe UMN signs (all regions, p≤0.034), but did not change longitudinally. Higher clinical UMN burden correlated with reduced CT, but not lower FD, for the bulbar region (p=2.2×10−10) and legs (p≤0.025). In the arms, we found that severe LMN signs may reduce the detectability of UMN signs (p≤0.043). With MRI, UMN degeneration was detectable before UMN signs became clinically evident (CT: p=1.1×10−10, FD: p=6.3×10−4). Motor CT, but not FD, deteriorated more than UMN signs during the study period.ConclusionsMotor CT is a more sensitive measure of UMN degeneration than UMN signs. Motor CT and pyramidal tract FD are discriminative between patients and controls. Brain MRI can monitor UMN degeneration before signs become clinically evident. These findings promote MRI as a potential biomarker for UMN progression in clinical trials in ALS.
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- 2022
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9. Characterising ALS disease progression according to El Escorial and Gold Coast criteria
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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
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BackgroundThe Gold Coast criteria (GCC) have been proposed as a means of selecting patients for amyotrophic lateral sclerosis (ALS) clinical trials. We aimed to characterise disease progression according to the GCC.MethodsData from population-based ALS registries from the Netherlands and Belgium were analysed. The GCC additionally define ALS as lower motor neuron (LMN) dysfunction in ≥2 body regions without upper motor neuron dysfunction. Therefore, the revised El Escorial criteria (rEEC) were supplemented with a ‘Gold Coast ALS’ category for patients with only LMN dysfunction in ≥2 body regions. We assessed survival time, ALS Functional Rating Scale (ALSFRS-R) progression rates and between-patient variability per diagnostic category.ResultsWe included 5957 ALS patients, of whom 600 (10.1%) fulfilled the GCC but not the rEEC, and 95 (1.6%) fulfilled only the rEEC. ALSFRS-R progression rates were similar for the rEEC (0.84 points/month) and GCC (0.81 points/month) with similar variability (standard deviation of 0.59 vs. 0.60) and median survival time (17.8 vs.18.7 months). Survival time and average progression rates varied (p<0.001) between categories. Per category, however, there was considerable between-patient variability with progression rates ranging from: −2.10 to −0.14 (definite), −1.94 to −0.06 (probable), −2.10 to −0.02 (probable laboratory supported), −1.79 to −0.02 (possible) and −1.31 to 0.08 (Gold Coast).ConclusionsThe GCC broaden the definition of ALS, allowing more patients to participate in trials, while minimally impacting population heterogeneity. Given the large variability per diagnostic category, selecting only specific categories for trials may not result in a more homogeneous study population.
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- 2022
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10. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
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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-García, Ricardo, 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, Andre 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 M., Groen, Ewout J. N., van Es, Michael A., Pasterkamp, R. Jeroen, Fan, Dongsheng, Garton, Fleur C., McRae, Allan F., Davey Smith, George, 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., and Veldink, Jan H.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
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- 2021
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11. Incidence, Prevalence and Geographical Clustering of Motor Neuron Disease in the Netherlands.
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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., and van den Berg, Leonard H.
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- 2021
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12. Multimodal longitudinal study of structural brain involvement in amyotrophic lateral sclerosis.
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van der Burgh, Hannelore K., Westeneng, Henk-Jan, Walhout, Renée, van Veenhuijzen, Kevin, Tan, Harold H. G., Meier, Jil M., Bakker, Leonhard A., Hendrikse, Jeroen, van Es, Michael A., Veldink, Jan H., van den Heuvel, Martijn P., and van den Berg, Leonard H.
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- 2020
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13. Prospective natural history study of ALS clinical characteristics and biomarkers.
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Cammack, Alexander J., Atassi, Nazem, Hyman, Theodore, van den Berg, Leonard H., Harms, Matthew, Baloh, Robert H., Brown, Robert H., van Es, Michael A., Veldink, Jan H., de Vries, Balint S., Rothstein, Jeffrey D., Drain, Caroline, Jockel-Balsarotti, Jennifer, Malcolm, Amber, Boodram, Sonia, Salter, Amber, Wightman, Nicholas, Hong Yu, Sherman, Alexander V., and Esparza, Thomas J.
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- 2019
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14. TDP-43 proteinopathies: a new wave of neurodegenerative diseases
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de Boer, Eva Maria Johanna, Orie, Viyanti K, Williams, Timothy, Baker, Mark R, De Oliveira, Hugo M, Polvikoski, Tuomo, Silsby, Matthew, Menon, Parvathi, van den Bos, Mehdi, Halliday, Glenda M, van den Berg, Leonard H, Van Den Bosch, Ludo, van Damme, Philip, Kiernan, Matthew, van Es, Michael A, and Vucic, Steve
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Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding (TARDBP) and unrelated genes (eg, C9orf72). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration.
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- 2021
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15. Use of Multimodal Imaging and Clinical Biomarkers in Presymptomatic Carriers of C9orf72 Repeat Expansion
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De Vocht, Joke, Blommaert, Jeroen, Devrome, Martijn, Radwan, Ahmed, Van Weehaeghe, Donatienne, De Schaepdryver, Maxim, Ceccarini, Jenny, Rezaei, Ahmadreza, Schramm, Georg, van Aalst, June, Chiò, Adriano, Pagani, Marco, Stam, Daphne, Van Esch, Hilde, Lamaire, Nikita, Verhaegen, Marianne, Mertens, Nathalie, Poesen, Koen, van den Berg, Leonard H., van Es, Michael A., Vandenberghe, Rik, Vandenbulcke, Mathieu, Van den Stock, Jan, Koole, Michel, Dupont, Patrick, Van Laere, Koen, and Van Damme, Philip
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IMPORTANCE: During a time with the potential for novel treatment strategies, early detection of disease manifestations at an individual level in presymptomatic carriers of a hexanucleotide repeat expansion in the C9orf72 gene (preSxC9) is becoming increasingly relevant. OBJECTIVES: To evaluate changes in glucose metabolism before symptom onset of amyotrophic lateral sclerosis or frontotemporal dementia in preSxC9 using simultaneous fluorine 18–labeled fluorodeoxyglucose ([18F]FDG positron emission tomographic (PET) and magnetic resonance imaging as well as the mutation’s association with clinical and fluid biomarkers. DESIGN, SETTING, AND PARTICIPANTS: A prospective, case-control study enrolled 46 participants from November 30, 2015, until December 11, 2018. The study was conducted at the neuromuscular reference center of the University Hospitals Leuven, Leuven, Belgium. MAIN OUTCOMES AND MEASURES: Neuroimaging data were spatially normalized and analyzed at the voxel level at a height threshold of P < .001, cluster-level familywise error–corrected threshold of P < .05, and statistical significance was set at P < .05 for the volume-of-interest level analysis, using Benjamini-Hochberg correction for multiple correction. W-score maps were computed using the individuals serving as controls as a reference to quantify the degree of [18F]FDG PET abnormality. The threshold for abnormality on the W-score maps was designated as an absolute W-score greater than or equal to 1.96. Neurofilament levels and performance on cognitive and neurologic examinations were determined. All hypothesis tests were 1-sided. RESULTS: Of the 42 included participants, there were 17 with the preSxC9 mutation (12 women [71%]; mean [SD] age, 51 [9] years) and 25 healthy controls (12 women [48%]; mean [SD] age, 47 [10] years). Compared with control participants, significant clusters of relative hypometabolism were found in frontotemporal regions, basal ganglia, and thalami of preSxC9 participants and relative hypermetabolism in the peri-Rolandic region, superior frontal gyrus, and precuneus cortex. W-score frequency maps revealed reduced glucose metabolism with local maxima in the insular cortices, central opercular cortex, and thalami in up to 82% of preSxC9 participants and increased glucose metabolism in the precentral gyrus and precuneus cortex in up to 71% of preSxC9 participants. Other findings in the preSxC9 group were upper motor neuron involvement in 10 participants (59%), cognitive abnormalities in 5 participants (29%), and elevated neurofilament levels in 3 of 16 individuals (19%) who underwent lumbar puncture. CONCLUSIONS AND RELEVANCE: The results suggest that [18F]FDG PET can identify glucose metabolic changes in preSxC9 at an individual level, preceding significantly elevated neurofilament levels and onset of symptoms.
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- 2020
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16. Pharmacogenetic interactions in amyotrophic lateral sclerosis: a step closer to a cure?
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van Eijk, Ruben P. A., Eijkemans, Marinus J. C., Nikolakopoulos, Stavros, Jansen, Marc D., Westeneng, Henk-Jan, van Eijk, Kristel R., van der Spek, Rick A. A., van Vugt, Joke J. F. A., Piepers, Sanne, Groeneveld, Geert-Jan, Veldink, Jan H., van den Berg, Leonard H., and van Es, Michael A.
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Genetic mutations related to amyotrophic lateral sclerosis (ALS) act through distinct pathophysiological pathways, which may lead to varying treatment responses. Here we assess the genetic interaction between C9orf72, UNC13A, and MOBPwith creatine and valproic acid treatment in two clinical trials. Genotypic data was available for 309 of the 338 participants (91.4%). The UNC13Agenotype affected mortality (p= 0.012), whereas C9orf72repeat-expansion carriers exhibited a faster rate of decline in overall (p= 0.051) and bulbar functioning (p= 0.005). A dose-response pharmacogenetic interaction was identified between creatine and the A allele of the MOBPgenotype (p= 0.027), suggesting a qualitative interaction in a recessive model (HR 3.96, p= 0.015). Not taking genetic information into account may mask evidence of response to treatment or be an unrecognized source of bias. Incorporating genetic data could help investigators to identify critical treatment clues in patients with ALS.
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- 2020
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17. Prognostic value of weight loss in patients with amyotrophic lateral sclerosis: a population-based study
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Janse van Mantgem, Mark R, van Eijk, Ruben P A, van der Burgh, Hannelore K, Tan, Harold H G, Westeneng, Henk-Jan, van Es, Michael A, Veldink, Jan H, and van den Berg, Leonard H
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ObjectiveTo determine the prevalence and prognostic value of weight loss (WL) prior to diagnosis in patients with amyotrophic lateral sclerosis (ALS).MethodsWe enrolled patients diagnosed with ALS between 2010 and 2018 in a population-based setting. At diagnosis, detailed information was obtained regarding the patient’s disease characteristics, anthropological changes, ALS-related genotypes and cognitive functioning. Complete survival data were obtained. Cox proportional hazard models were used to assess the association between WL and the risk of death during follow-up.ResultsThe data set comprised 2420 patients of whom 67.5% reported WL at diagnosis. WL occurred in 71.8% of the bulbar-onset and in 64.2% of the spinal-onset patients; the mean loss of body weight was 6.9% (95% CI 6.8 to 6.9) and 5.5% (95% CI 5.5 to 5.6), respectively (p<0.001). WL occurred in 35.1% of the patients without any symptom of dysphagia. WL is a strong independent predictor of survival, with a dose response relationship between the amount of WL and the risk of death: the risk of death during follow-up increased by 23% for every 10% increase in WL relative to body weight (HR 1.23, 95% CI 1.13 to 1.51, p<0.001).ConclusionsThis population-based study shows that two-thirds of the patients with ALS have WL at diagnosis, which also occurs independent of dysphagia, and is related to survival. Our results suggest that WL is a multifactorial process that may differ from patient to patient. Gaining further insight in its underlying factors could prove essential for future therapeutic measures.
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- 2020
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18. KIF1Avariants are a frequent cause of autosomal dominant hereditary spastic paraplegia
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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
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Variants in the KIF1Agene can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal (de novo) dominant mental retardation type 9. More recently, variants in KIF1Ahave also been described in a few cases with autosomal dominant spastic paraplegia. Here, we describe 20 KIF1Avariants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly ‘pure’ spastic paraplegia. In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0–57 years). Segregation analyses showed a de novo occurrence in seven cases, and a dominant inheritance pattern in 11 families. The motor domain of KIF1A is a hotspot for disease causing variants in autosomal dominant spastic paraplegia, similar to mental retardation type 9 and recessive spastic paraplegia type 30. However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families. Finally, three missense variants were outside the motor domain and need further characterization. In conclusion, KIF1Avariants are a frequent cause of autosomal dominant spastic paraplegia in our cohort (6–7%). The identification of KIF1Aloss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic paraplegia.
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- 2020
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19. Development and assessment of the inter-rater and intra-rater reproducibility of a self-administration version of the ALSFRS-R
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Bakker, Leonhard A, Schro¨der, Carin D, Tan, Harold H G, Vugts, Simone M A G, van Eijk, Ruben P A, van Es, Michael A, Visser-Meily, Johanna M A, and van den Berg, Leonard H
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ObjectiveThe Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is widely applied to assess disease severity and progression in patients with motor neuron disease (MND). The objective of the study is to assess the inter-rater and intra-rater reproducibility, i.e., the inter-rater and intra-rater reliability and agreement, of a self-administration version of the ALSFRS-R for use in apps, online platforms, clinical care and trials.MethodsThe self-administration version of the ALSFRS-R was developed based on both patient and expert feedback. To assess the inter-rater reproducibility, 59 patients with MND filled out the ALSFRS-R online and were subsequently assessed on the ALSFRS-R by three raters. To assess the intra-rater reproducibility, patients were invited on two occasions to complete the ALSFRS-R online. Reliability was assessed with intraclass correlation coefficients, agreement was assessed with Bland-Altman plots and paired samples t-tests, and internal consistency was examined with Cronbach’s coefficient alpha.ResultsThe self-administration version of the ALSFRS-R demonstrated excellent inter-rater and intra-rater reliability. The assessment of inter-rater agreement demonstrated small systematic differences between patients and raters and acceptable limits of agreement. The assessment of intra-rater agreement demonstrated no systematic changes between time points; limits of agreement were 4.3 points for the total score and ranged from 1.6 to 2.4 points for the domain scores. Coefficient alpha values were acceptable.DiscussionThe self-administration version of the ALSFRS-R demonstrates high reproducibility and can be used in apps and online portals for both individual comparisons, facilitating the management of clinical care and group comparisons in clinical trials.
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- 2020
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20. Cognitive and behavioural changes in PLS and PMA:challenging the concept of restricted phenotypes
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de Vries, Bálint S, Rustemeijer, Laura M M, Bakker, Leonhard A, Schro¨der, Carin D, Veldink, Jan H, van den Berg, Leonard H, Nijboer, Tanja C W, and van Es, Michael A
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ObjectivesCognitive and behavioural changes within the spectrum of frontotemporal dementia (FTD) are observed frequently in patients with amyotrophic lateral sclerosis (ALS). Whether these changes also occur in other forms of motor neuron disease (MND) is not well studied. We therefore systemically screened a large cohort of patients with primary lateral sclerosis (PLS) and progressive muscular atrophy (PMA) for cognitive and behavioural changes, and subsequently compared our findings with a cohort of patients with ALS.MethodsUsing a set of screening instruments (Edinburgh Cognitive and Behavioural ALS Screen, ALS and Frontotemporal Dementia Questionnaire, Frontal Assessment Battery, and Hospital Anxiety and Depression Scale), the presence of cognitive and behavioural changes as well as anxiety and depression in 277 patients with ALS, 75 patients with PLS and 143 patients with PMA was evaluated retrospectively.ResultsWe found a high frequency of cognitive and behavioural abnormalities with similar profiles in all three groups. Subjects with behavioural variant FTD were identified in all groups.ConclusionsThe percentage of patients with PLS and PMA with cognitive dysfunction was similar to patients with ALS, emphasising the importance for cognitive screening as part of routine clinical care in all three patient groups. With a similar cognitive profile, in line with genetic and clinical overlap between the MNDs, the view of PLS as an MND exclusively affecting upper motor neurons and PMA exclusively affecting lower motor neurons cannot be held. Therefore, our findings are in contrast to the recently revised El Escorial criteria of 2015, where PLS and PMA are described as restricted phenotypes. Our study favours a view of PLS and PMA as multidomain diseases similar to ALS.
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- 2019
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21. Distinctive pattern of temporal atrophy in patients with frontotemporal dementia and the I383V variant in TARDBP
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Mol, Merel O., Nijmeijer, Sebastiaan W.R., van Rooij, Jeroen G. J., van Spaendonk, Resie M. L., Pijnenburg, Yolande A. L., van der Lee, Sven J., van Minkelen, Rick, Donker Kaat, Laura, Rozemuller, Annemieke J. M., Janse van Mantgem, Mark R., van Rheenen, Wouter, van Es, Michael A., Veldink, Jan H., Hennekam, Frederic A. M., Vernooij, Meike, van Swieten, John C., Cohn-Hokke, Petra E., Seelaar, Harro, and Dopper, Elise G.P.
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- 2021
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22. Diagnostic value of sonography in treatment-naive chronic inflammatory neuropathies.
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Goedee, H. Stephan, van der Pol, W. Ludo, van Asseldonk, Jan-Thies H., Franssen, Hessel, Notermans, Nicolette C., Vrancken, Alexander J. F. E., van Es, Michael A., Nikolakopoulos, Stavros, Visser, Leo H., and van den Berg, Leonard H.
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- 2017
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23. Amyotrophic lateral sclerosis
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van Es, Michael A, Hardiman, Orla, Chio, Adriano, Al-Chalabi, Ammar, Pasterkamp, R Jeroen, Veldink, Jan H, and van den Berg, Leonard H
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Amyotrophic lateral sclerosis is characterised by the progressive loss of motor neurons in the brain and spinal cord. This neurodegenerative syndrome shares pathobiological features with frontotemporal dementia and, indeed, many patients show features of both diseases. Many different genes and pathophysiological processes contribute to the disease, and it will be necessary to understand this heterogeneity to find effective treatments. In this Seminar, we discuss clinical and diagnostic approaches as well as scientific advances in the research fields of genetics, disease modelling, biomarkers, and therapeutic strategies.
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- 2017
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24. Brain morphologic changes in asymptomatic C9orf72 repeat expansion carriers.
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Walhout, Renée, Schmidt, Ruben, Westeneng, Henk-Jan, Verstraete, Esther, Seelen, Meinie, van Rheenen, Wouter, de Reus, Marcel A., van Es, Michael A., Hendrikse, Jeroen, Veldink, Jan H., van den Heuvel, Martijn P., and van den Berg, Leonard H.
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- 2015
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25. Diagnostic value of sonography in treatment-naive chronic inflammatory neuropathies
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Goedee, H. Stephan, van der Pol, W. Ludo, van Asseldonk, Jan-Thies H., Franssen, Hessel, Notermans, Nicolette C., Vrancken, Alexander J.F.E., van Es, Michael A., Nikolakopoulos, Stavros, Visser, Leo H., and van den Berg, Leonard H.
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- 2017
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26. Detection of long repeat expansions from PCR-free whole-genome sequence data
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Dolzhenko, Egor, van Vugt, Joke J.F.A., Shaw, Richard J., Bekritsky, Mitchell A., van Blitterswijk, Marka, Narzisi, Giuseppe, Ajay, Subramanian S., Rajan, Vani, Lajoie, Bryan R., Johnson, Nathan H., Kingsbury, Zoya, Humphray, Sean J., Schellevis, Raymond D., Brands, William J., Baker, Matt, Rademakers, Rosa, Kooyman, Maarten, Tazelaar, Gijs H.P., van Es, Michael A., McLaughlin, Russell, Sproviero, William, Shatunov, Aleksey, Jones, Ashley, Al Khleifat, Ahmad, Pittman, Alan, Morgan, Sarah, Hardiman, Orla, Al-Chalabi, Ammar, Shaw, Chris, Smith, Bradley, Neo, Edmund J., Morrison, Karen, Shaw, Pamela J., Reeves, Catherine, Winterkorn, Lara, Wexler, Nancy S., Housman, David E., Ng, Christopher W., Li, Alina L., Taft, Ryan J., van den Berg, Leonard H., Bentley, David R., Veldink, Jan H., and Eberle, Michael A.
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Identifying large expansions of short tandem repeats (STRs), such as those that cause amyotrophic lateral sclerosis (ALS) and fragile X syndrome, is challenging for short-read whole-genome sequencing (WGS) data. A solution to this problem is an important step toward integrating WGS into precision medicine. We developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3001 ALS patients who have been tested for the presence of the C9orf72repeat expansion with repeat-primed PCR (RP-PCR). Compared against this truth data, ExpansionHunter correctly classified all (212/212, 95% CI [0.98, 1.00]) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2786/2789, 95% CI [0.997, 1.00]) of the wild-type samples were correctly classified as wild type by this method with the remaining three samples identified as possible expansions. We further applied our algorithm to a set of 152 samples in which every sample had one of eight different pathogenic repeat expansions, including those associated with fragile X syndrome, Friedreich's ataxia, and Huntington's disease, and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions.
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- 2017
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27. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
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van Rheenen, Wouter, Shatunov, Aleksey, Dekker, Annelot M, McLaughlin, Russell L, Diekstra, Frank P, Pulit, Sara L, van der Spek, Rick A A, Võsa, Urmo, de Jong, Simone, Robinson, Matthew R, Yang, Jian, Fogh, Isabella, van Doormaal, Perry TC, Tazelaar, Gijs H P, Koppers, Max, Blokhuis, Anna M, Sproviero, William, Jones, Ashley R, Kenna, Kevin P, van Eijk, Kristel R, Harschnitz, Oliver, Schellevis, Raymond D, Brands, William J, Medic, Jelena, Menelaou, Androniki, Vajda, Alice, Ticozzi, Nicola, Lin, Kuang, Rogelj, Boris, Vrabec, Katarina, Ravnik-Glavač, Metka, Koritnik, Blaž, Zidar, Janez, Leonardis, Lea, Grošelj, Leja Dolenc, Millecamps, Stéphanie, Salachas, François, Meininger, Vincent, de Carvalho, Mamede, Pinto, Susana, Mora, Jesus S, Rojas-García, Ricardo, Polak, Meraida, Chandran, Siddharthan, Colville, Shuna, Swingler, Robert, Morrison, Karen E, Shaw, Pamela J, Hardy, John, Orrell, Richard W, Pittman, Alan, Sidle, Katie, Fratta, Pietro, Malaspina, Andrea, Topp, Simon, Petri, Susanne, Abdulla, Susanne, Drepper, Carsten, Sendtner, Michael, Meyer, Thomas, Ophoff, Roel A, Staats, Kim A, Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, Van Deerlin, Vivianna M, Trojanowski, John Q, Elman, Lauren, McCluskey, Leo, Basak, A Nazli, Tunca, Ceren, Hamzeiy, Hamid, Parman, Yesim, Meitinger, Thomas, Lichtner, Peter, Radivojkov-Blagojevic, Milena, Andres, Christian R, Maurel, Cindy, Bensimon, Gilbert, Landwehrmeyer, Bernhard, Brice, Alexis, Payan, Christine A M, Saker-Delye, Safaa, Dürr, Alexandra, Wood, Nicholas W, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M, Amouyel, Philippe, Tzourio, Christophe, Dartigues, Jean-François, Uitterlinden, Andre G, Rivadeneira, Fernando, Estrada, Karol, Hofman, Albert, Curtis, Charles, Blauw, Hylke M, van der Kooi, Anneke J, de Visser, Marianne, Goris, An, Weber, Markus, Shaw, Christopher E, Smith, Bradley N, Pansarasa, Orietta, Cereda, Cristina, Del Bo, Roberto, Comi, Giacomo P, D'Alfonso, Sandra, Bertolin, Cinzia, Sorarù, Gianni, Mazzini, Letizia, Pensato, Viviana, Gellera, Cinzia, Tiloca, Cinzia, Ratti, Antonia, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Arcuti, Simona, Capozzo, Rosa, Zecca, Chiara, Lunetta, Christian, Penco, Silvana, Riva, Nilo, Padovani, Alessandro, Filosto, Massimiliano, Muller, Bernard, Stuit, Robbert Jan, Blair, Ian, Zhang, Katharine, McCann, Emily P, Fifita, Jennifer A, Nicholson, Garth A, Rowe, Dominic B, Pamphlett, Roger, Kiernan, Matthew C, Grosskreutz, Julian, Witte, Otto W, Ringer, Thomas, Prell, Tino, Stubendorff, Beatrice, Kurth, Ingo, Hübner, Christian A, Leigh, P Nigel, Casale, Federico, Chio, Adriano, Beghi, Ettore, Pupillo, Elisabetta, Tortelli, Rosanna, Logroscino, Giancarlo, Powell, John, Ludolph, Albert C, Weishaupt, Jochen H, Robberecht, Wim, Van Damme, Philip, Franke, Lude, Pers, Tune H, Brown, Robert H, Glass, Jonathan D, Landers, John E, Hardiman, Orla, Andersen, Peter M, Corcia, Philippe, Vourc'h, Patrick, Silani, Vincenzo, Wray, Naomi R, Visscher, Peter M, de Bakker, Paul I W, van Es, Michael A, Pasterkamp, R Jeroen, Lewis, Cathryn M, Breen, Gerome, Al-Chalabi, Ammar, van den Berg, Leonard H, and Veldink, Jan H
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To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1–10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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- 2016
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28. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis
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Kenna, Kevin P, van Doormaal, Perry T C, Dekker, Annelot M, Ticozzi, Nicola, Kenna, Brendan J, Diekstra, Frank P, van Rheenen, Wouter, van Eijk, Kristel R, Jones, Ashley R, Keagle, Pamela, Shatunov, Aleksey, Sproviero, William, Smith, Bradley N, van Es, Michael A, Topp, Simon D, Kenna, Aoife, Miller, Jack W, Fallini, Claudia, Tiloca, Cinzia, McLaughlin, Russell L, Vance, Caroline, Troakes, Claire, Colombrita, Claudia, Mora, Gabriele, Calvo, Andrea, Verde, Federico, Al-Sarraj, Safa, King, Andrew, Calini, Daniela, de Belleroche, Jacqueline, Baas, Frank, van der Kooi, Anneke J, de Visser, Marianne, ten Asbroek, Anneloor L M A, Sapp, Peter C, McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Muñoz-Blanco, José Luis, Strom, Tim M, Meitinger, Thomas, Morrison, Karen E, Lauria, Giuseppe, Williams, Kelly L, Leigh, P Nigel, Nicholson, Garth A, Blair, Ian P, Leblond, Claire S, Dion, Patrick A, Rouleau, Guy A, Pall, Hardev, Shaw, Pamela J, Turner, Martin R, Talbot, Kevin, Taroni, Franco, Boylan, Kevin B, Van Blitterswijk, Marka, Rademakers, Rosa, Esteban-Pérez, Jesús, García-Redondo, Alberto, Van Damme, Phillip, Robberecht, Wim, Chio, Adriano, Gellera, Cinzia, Drepper, Carsten, Sendtner, Michael, Ratti, Antonia, Glass, Jonathan D, Mora, Jesús S, Basak, Nazli A, Hardiman, Orla, Ludolph, Albert C, Andersen, Peter M, Weishaupt, Jochen H, Brown, Robert H, Al-Chalabi, Ammar, Silani, Vincenzo, Shaw, Christopher E, van den Berg, Leonard H, Veldink, Jan H, and Landers, John E
- Abstract
To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.
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- 2016
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29. Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis
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Fogh, Isabella, Lin, Kuang, Tiloca, Cinzia, Rooney, James, Gellera, Cinzia, Diekstra, Frank P., Ratti, Antonia, Shatunov, Aleksey, van Es, Michael A., Proitsi, Petroula, Jones, Ashley, Sproviero, William, Chiò, Adriano, McLaughlin, Russell Lewis, Sorarù, Gianni, Corrado, Lucia, Stahl, Daniel, Del Bo, Roberto, Cereda, Cristina, Castellotti, Barbara, Glass, Jonathan D., Newhouse, Steven, Dobson, Richard, Smith, Bradley N., Topp, Simon, van Rheenen, Wouter, Meininger, Vincent, Melki, Judith, Morrison, Karen E., Shaw, Pamela J., Leigh, P. Nigel, Andersen, Peter M., Comi, Giacomo P., Ticozzi, Nicola, Mazzini, Letizia, D’Alfonso, Sandra, Traynor, Bryan J., Van Damme, Philip, Robberecht, Wim, Brown, Robert H., Landers, John E., Hardiman, Orla, Lewis, Cathryn M., van den Berg, Leonard H., Shaw, Christopher E., Veldink, Jan H., Silani, Vincenzo, Al-Chalabi, Ammar, and Powell, John
- Abstract
IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset. OBJECTIVE: To identify gene variants influencing survival in ALS. DESIGN, SETTING, AND PARTICIPANTS: This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7 174 392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015. MAIN OUTCOMES AND MEASURES: Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed by meta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis. RESULTS: Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 [12] years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P = 1.87 × 10−9) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 × 10−8). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38-1.89; P = 1.87 × 10−9), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208 CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11-1.24; P = 3.53 × 10−8), corresponding to a 4-month reduction in survival compared with TT carriers. CONCLUSIONS AND RELEVANCE: This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not feasible, treatment that modifies survival is the most realistic strategy. Therefore, identification of modifier genes that might influence ALS survival could improve the understanding of the biology of the disease and suggest biological targets for pharmaceutical intervention. In addition, genetic risk scores for survival could be used as an adjunct to clinical trials to account for the genetic contribution to survival.
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- 2016
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30. Brain morphologic changes in asymptomatic C9orf72repeat expansion carriers
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Walhout, Renée, Schmidt, Ruben, Westeneng, Henk-Jan, Verstraete, Esther, Seelen, Meinie, van Rheenen, Wouter, de Reus, Marcel A., van Es, Michael A., Hendrikse, Jeroen, Veldink, Jan H., van den Heuvel, Martijn P., and van den Berg, Leonard H.
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- 2015
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31. Author Correction: Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
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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-García, Ricardo, 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, Andre 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 M., Groen, Ewout J. N., van Es, Michael A., Pasterkamp, R. Jeroen, Fan, Dongsheng, Garton, Fleur C., McRae, Allan F., Davey Smith, George, 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., and Veldink, Jan H.
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- 2022
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32. Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
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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., van Eijk, Kristel R., Moisse, Matthieu, Baird, Denis, Al Khleifat, Ahmad, Iacoangeli, Alfredo, 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, de 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, Wray, Naomi R., McLaughlin, Russell L., Hardiman, Orla, Kenna, Kevin P., Tsai, Ellen, Runz, Heiko, Al-Chalabi, Ammar, van den Berg, Leonard H., Van Damme, Philip, Mill, Jonathan, Veldink, Jan H., Veldink, Jan H., van den Berg, Leonard H., Moed, Matthijs, Al-Chalabi, Ammar, Wray, Naomi R., Hardiman, Orla, Chio, Adriano, and Mill, Jonathan
- Abstract
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.
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- 2022
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33. A cosegregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorderHow to Cite this Article: van der Zwaag B, Staal WG, Hochstenbach R, Poot M, Spierenburg HA, de Jonge MV, Verbeek NE, van t Slot R, van Es MA, Staal FJ, Freitag CM, BuizerVoskamp JE, Nelen MR, van den Berg LH, van Amstel HKP, van Engeland H, Burbach JPH. 2010. A Cosegregating Microduplication of Chromosome 15q11.2 Pinpoints Two Risk Genes for Autism Spectrum Disorder. Am J Med Genet Part B 153B: 960–966.
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van der Zwaag, Bert, Staal, Wouter G., Hochstenbach, Ron, Poot, Martin, Spierenburg, Henk A., de Jonge, Maretha V., Verbeek, Nienke E., van t Slot, Ruben, van Es, Michael A., Staal, Frank J., Freitag, Christine M., BuizerVoskamp, Jacobine E., Nelen, Marcel R., van den Berg, Leonard H., van Amstel, Hans K. Ploos, van Engeland, Herman, and Burbach, J. Peter H.
- Abstract
High resolution genomic copynumber analysis has shown that inherited and de novo copynumber variations contribute significantly to autism pathology, and that identification of small chromosomal aberrations related to autism will expedite the discovery of risk genes involved. Here, we report a microduplication of chromosome 15q11.2, spanning only four genes, cosegregating with autism in a Dutch pedigree, identified by SNP microarray analysis, and independently confirmed by FISH and MLPA analysis. Quantitative RTPCR analysis revealed over 70 increase in peripheral blood mRNA levels for the four genes present in the duplicated region in patients, and RNA in situ hybridization on mouse embryonic and adult brain sections revealed that two of the four genes, CYFIP1and NIPA1, were highly expressed in the developing mouse brain. These findings point towards a contribution of microduplications at chromosome 15q11.2 to autism, and highlight CYFIP1and NIPA1as autism risk genes functioning in axonogenesis and synaptogenesis. Thereby, these findings further implicate defects in dosagesensitive molecular control of neuronal connectivity in autism. However, the prevalence of this microduplication in patient samples was statistically not significantly different from control samples 0.94 in patients vs. 0.42 controls, P 0.247, which suggests that our findings should be interpreted with caution and indicates the need for studies that include large numbers of control subjects to ascertain the impact of these changes on a population scale. © 2009 WileyLiss, Inc.
- Published
- 2010
- Full Text
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34. FUS Mutations in Familial Amyotrophic Lateral Sclerosis in the NetherlandsFUS Mutations in FALS
- Author
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Groen, Ewout J. N., van Es, Michael A., van Vught, Paul W. J., Spliet, Wim G. M., van Engelen-Lee, Jooyeon, de Visser, Marianne, Wokke, John H. J., Schelhaas, Helenius J., Ophoff, Roel A., Fumoto, Katsumi, Pasterkamp, R. Jeroen, Dooijes, Dennis, Cuppen, Edwin, Veldink, Jan H., and van den Berg, Leonard H.
- Abstract
OBJECTIVES To assess the frequency of FUS mutations in 52 probands with familial amyotrophic lateral sclerosis (FALS) and to provide careful documentation of clinical characteristics. DESIGN FUS mutation analysis was performed using capillary sequencing on all coding regions of the gene in a cohort of patients with FALS. The clinical characteristics of patients carrying FUS mutations were described in detail. SETTING Three university hospitals in the Netherlands (referral centers for neuromuscular diseases). PATIENTS Fifty-two probands from unrelated pedigrees with FALS. MAIN OUTCOME MEASURE FUS mutations. RESULTS We identified 3 mutations in 4 of 52 probands. We observed 2 previously identified mutations (p.Arg521Cys and p.Arg521His) and 1 novel mutation (p.Ser462Phe). In addition, a p.Gln210His polymorphism was identified in 1 proband and 3 healthy control subjects. Phenotypic analysis demonstrated that patients may lack upper motor neuron signs, which was confirmed at autopsy, and disease survival was short (<36 months for 8 of 10 patients). CONCLUSIONS We discovered FUS mutations in Dutch patients with FALS and the occurrence of benign variations in the gene. Therefore, caution is warranted when interpreting results in a clinical setting. Although the phenotype associated with FUS mutations is variable, most patients predominantly demonstrate loss of lower motor neurons and have short disease survival.Arch Neurol. 2010;67(2):224-230--
- Published
- 2010
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35. Refining eligibility criteria for amyotrophic lateral sclerosis clinical trials.
- Author
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van Eijk, Ruben P. A., Westeneng, Henk-Jan, Nikolakopoulos, Stavros, Verhagen, Iris E, van Es, Michael A, Eijkemans, Marinus J C, and van den Berg, Leonard H
- Published
- 2019
- Full Text
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36. Nepal's Constitutional Standoff Threatens Its Transition.
- Author
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Vurens van Es, Michael
- Subjects
PUBLIC demonstrations ,CONSTITUTIONS ,POLITICAL systems ,NEPALI politics & government ,POLITICAL parties - Abstract
The article discusses the unstable situation in Nepal following the failure of a 2nd Constituent Assembly to announce a constitution before January 22, 2015. Topics cited include the impact of the ongoing protests on the country's commerce, the importance of ramifications for the constitution's credibility and the apparent minimal feats achieved in February 2014 by the Nepali Congress and the social democratic Communist Party of Nepal (Unified Marxist Leninist), known as CPN-UML.
- Published
- 2015
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