148 results on '"van Es Ma"'
Search Results
2. Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS.
- Author
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Taskesen, E, Mishra, A, van der Sluis, S, Ferrari, R, International FTD-Genomics Consortium, Veldink, JH, van Es, MA, Smit, AB, Posthuma, D, and Pijnenburg, Y
- Subjects
International FTD-Genomics Consortium ,Frontotemporal Dementia (FTD) ,Acquired Cognitive Impairment ,Neurodegenerative ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Brain Disorders ,Dementia ,ALS ,Human Genome ,Rare Diseases ,Neurosciences ,Genetics ,Alzheimer's Disease Related Dementias (ADRD) ,2.1 Biological and endogenous factors ,Neurological - Abstract
Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent epigenetic factors contribute to FTD and whether these factors vary between FTD clinical subgroup. We compared the DNA-methylation levels of FTD cases (n = 128), and of FTD cases with Amyotrophic Lateral Sclerosis (FTD-ALS; n = 7) to those of unaffected controls (n = 193), which resulted in 14 and 224 candidate genes, respectively. Cluster analysis revealed significant class separation of FTD-ALS from controls. We could further specify genes with increased susceptibility for abnormal gene-transcript behavior by jointly analyzing DNA-methylation levels with the presence of mutations in a GWAS FTD-cohort. For FTD-ALS, this resulted in 9 potential candidate genes, whereas for FTD we detected 1 candidate gene (ELP2). Independent validation-sets confirmed the genes DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35, and ELP2/SLC39A6 among others. We could furthermore demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.
- Published
- 2017
3. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology (vol 53, pg 1636, 2021)
- Author
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van Rheenen, W, van der Spek, RAA, Bakker, MK, van Vugt, JJFA, Hop, PJ, Zwamborn, RAJ, de Klein, N, Westra, HJ, Bakker, OB, Deelen, P, Shireby, G, Hannon, E, Moisse, M, Baird, D, Restuadi, R, Dolzhenko, E, Dekker, AM, Gawor, K, Westeneng, HJ, Tazelaar, GHP, van Eijk, KR, Kooyman, M, Byrne, RP, Doherty, M, Heverin, M, Al Khleifat, A, Iacoangeli, A, Shatunov, A, Ticozzi, N, Cooper-Knock, J, Smith, BN, Gromicho, M, Chandran, S, Pal, S, Morrison, KE, Shaw, PJ, Hardy, J, Orrell, RW, Sendtner, M, Meyer, T, Basak, N, van der Kooi, AJ, Ratti, A, Fogh, I, Gellera, C, Lauria, G, Corti, S, Cereda, C, Sproviero, D, Soraru, G, Siciliano, G, Filosto, M, Padovani, A, Chio, A, Calvo, A, Moglia, C, Brunetti, M, Canosa, A, Grassano, M, Beghi, E, Pupillo, E, Logroscino, G, Nefussy, B, Osmanovic, A, Nordin, A, Lerner, Y, Zabari, M, Gotkine, M, Baloh, RH, Bell, S, Vourc'h, P, Corcia, P, Couratier, P, Millecamps, S, Meininger, V, Salachas, F, Pardina, JMS, Assialioui, A, Rojas-Garcia, R, Dion, PA, Ross, JP, Ludolph, AC, Weishaupt, JH, Brenner, D, Freischmidt, A, Bensimon, G, Brice, A, Durr, A, Payan, CAM, Saker-Delye, S, Wood, NW, Topp, S, Rademakers, R, Tittmann, L, Lieb, W, Franke, A, Ripke, S, Braun, A, Kraft, J, Whiteman, DC, Olsen, CM, Uitterlinden, AG, Hofman, A, Rietschel, M, Cichon, S, Nothen, MM, Amouyel, P, Comi, G, Riva, N, Lunetta, C, Gerardi, F, Cotelli, MS, Rinaldi, F, Chiveri, L, Guaita, MC, Perrone, P, Diamanti, L, Ferrarese, C, Tremolizzo, L, Delodovici, ML, Bono, G, Manera, U, Vasta, R, Bombaci, A, Casale, F, Fuda, G, Salamone, P, Iazzolino, B, Peotta, L, Cugnasco, P, De Marco, G, Torrieri, MC, Palumbo, F, Gallone, S, Barberis, M, Sbaiz, L, Gentile, S, Mauro, A, De Marchi, F, D'Alfonso, S, Bertolotto, A, Gionco, M, Leotta, D, Odddenino, E, Imperiale, D, Cavallo, R, Pignatta, P, De Mattei, M, Geda, C, Papurello, DM, Gusmaroli, G, Comi, C, Labate, C, Ruiz, L, Ferrandi, D, Rota, E, Aguggia, M, Di Vito, N, Meineri, P, Ghiglione, P, Launaro, N, Dotta, M, Di Sapio, A, Giardini, G, Tiloca, C, Peverelli, S, Taroni, F, Pensato, V, Castellotti, B, Comi, GP, Del Bo, R, Ceroni, M, Gagliardi, S, Corrado, L, Mazzini, L, Raggi, F, Simoncini, C, Lo Gerfo, A, Inghilleri, M, Ferlini, A, Simone, IL, Passarella, B, Guerra, V, Zoccolella, S, Nozzoli, C, Mundi, C, Leone, M, Zarrelli, M, Tamma, F, Valluzzi, F, Calabrese, G, Boero, G, Rini, A, Traynor, BJ, Singleton, AB, Neto, MM, Cauchi, RJ, Ophoff, RA, Wiedau-Pazos, M, Lomen-Hoerth, C, van Deerlin, VM, Grosskreutz, J, Roediger, A, Gaur, N, Jork, A, Barthel, T, Theele, E, Ilse, B, Stubendorff, B, Witte, OW, Steinbach, R, Hubner, CA, Graff, C, Brylev, L, Fominykh, V, Demeshonok, V, Ataulina, A, Rogelj, B, Koritnik, B, Zidar, J, Ravnik-Glavac, M, Glavac, D, Stevic, Z, Drory, V, Povedano, M, Blair, IP, Kiernan, MC, Benyamin, B, Henderson, RD, Furlong, S, Mathers, S, McCombe, PA, Needham, M, Ngo, ST, Nicholson, GA, Pamphlett, R, Rowe, DB, Steyn, FJ, Williams, KL, Mather, KA, Sachdev, PS, Henders, AK, Wallace, L, de Carvalho, M, Pinto, S, Petri, S, Weber, M, Rouleau, GA, Silani, V, Curtis, CJ, Breen, G, Glass, JD, Brown, RH, Landers, JE, Shaw, CE, Andersen, PM, Groen, EJN, van Es, MA, Pasterkamp, RJ, Fan, DS, Garton, FC, McRae, AF, Smith, GD, Gaunt, TR, Eberle, MA, Mill, J, McLaughlin, RL, Hardiman, O, Kenna, KP, Wray, NR, Tsai, EL, Runz, H, Franke, L, Al-Chalabi, A, Van Damme, P, van den Berg, LH, Veldink, JH, SLALOM Consortium, PARALS Consortium, SLAGEN Consortium, and SLAP Consortium
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- 2022
4. Genome-wide study of DNA methylation in Amyotrophic Lateral Sclerosis identifies differentially methylated loci and implicates metabolic, inflammatory and cholesterol pathways
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Orla Hardiman, Karen E. Morrison, Johnathan Cooper-Knock, Susan Mathers, Matthieu Moisse, Kevin P. Kenna, Michal Zabari, Ruben J. Cauchi, Jonathan Mill, Maurizio Grassano, Paul J. Hop, de Carvalho M, Allan F. McRae, John Landers, Heiko Runz, Basak An, Lerner Y, Mònica Povedano, Drory, Patrick Vourc'h, Philippe Couratier, van Rheenen W, Jan H. Veldink, Denis Baird, Antonia Ratti, Van Damme P, Garth A. Nicholson, Andrea Calvo, van Vugt Jj, Nicola Ticozzi, Eilis Hannon, Antonio Canosa, Silani, Matthew C. Kiernan, Ian P. Blair, Guy A. Rouleau, Mitne Neto M, Kelly L. Williams, Christopher Shaw, Emma Walker, Markus Weber, Frederik J. Steyn, Anjali K. Henders, Peter M. Andersen, Marta F. Nabais, Henk-Jan Westeneng, Dominic B. Rowe, Ramona A. J. Zwamborn, Salas T, Susana Pinto, Shyuan T. Ngo, van den Berg Lh, Sarah Furlong, Adriano Chiò, Mora Pardina Js, Marc Gotkine, Leanne Wallace, Al Khleifat A, Naomi R. Wray, Tian Lin, Roger Pamphlett, Ellen A. Tsai, Alfredo Iacoangeli, Gijs H.P. Tazelaar, Robert D. Henderson, van Es Ma, Pamela J. Shaw, Annelot M. Dekker, Ammar Al-Chalabi, Pamela A. McCombe, Maura Brunetti, Merrilee Needham, Philippe Corcia, Karen A. Mather, Gemma Shireby, Jay P. Ross, Russell L. McLaughlin, Pasterkamp Rj, van Eijk Kr, Patrick A. Dion, Cristina Moglia, Perminder S. Sachdev, and Fleur C. Garton
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Genetics ,Genome-wide association study ,Disease ,Biology ,medicine.disease ,Genome ,Blood cell ,medicine.anatomical_structure ,White blood cell ,DNA methylation ,Brain MEND Consortium ,medicine ,BIOS Consortium ,Amyotrophic lateral sclerosis ,Gene - Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability of around 50%. DNA methylation patterns can serve as biomarkers 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 (EWAS) meta-analysis in 10,462 samples (7,344 ALS patients and 3,118 controls), representing the largest case-control study of DNA methylation for any disease to date. 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 show that DNA-methylation-based proxies for HDL-cholesterol, BMI, white blood cell (WBC) proportions and alcohol intake were independently associated with ALS. Integration of these results with our latest GWAS showed that cholesterol biosynthesis was causally related to ALS. Finally, we found that DNA methylation levels at several DMPs and blood cell proportion estimates derived from DNA methylation data, are associated with survival rate in patients, and could represent indicators of underlying disease processes.
- Published
- 2021
5. CHCHD10 variants in amyotrophic lateral sclerosis: where is the evidence?
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Tazelaar, GHP, van Rheenen, W, Pulit, SL, van der Spek, RAA, Dekker, AM, Moisse, M, McLaughlin, RL, Sproviero, W, Kenna, KP, Kooyman, M, van Doormaal, PTC, van Eijk, KE, Middelkoop, BM, Schellevis, RD, Brands, WJ, Al-Chalabi, A, Morrison, KE, Shaw, PJ, Shaw, CE, Newhouse, SE, van Es, MA, Basak, AN, Akçimen, F, Kocoglu, C, Tunca, C, Povedano, M, Mora, JS, Glass, JD, Van Damme, P, Robberecht, W, HardimanMD, O, Landers, JE, van den Berg, LH, and Veldink, JH
- Abstract
© 2018 American Neurological Association 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. Also, 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. Ann Neurol 2018;83:110–116. ispartof: Annals of Neurology vol:84 issue:1 pages:110-116 ispartof: location:United States status: published
- Published
- 2018
6. A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis
- Author
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Fogh I, Ratti A, Gellera C, Lin K, Tiloca C, Moskvina V, Corrado L, Sorarù G, Cereda C, Corti S, Gentilini D, Calini D, Castellotti B, Mazzini L, Querin G, Gagliardi S, Del Bo R, Conforti FL, Siciliano G, Inghilleri M, Saccà F, Bongioanni P, Penco S, Corbo M, Sorbi S, Filosto M, Ferlini A, Di Blasio AM, Signorini S, Shatunov A, Jones A, Shaw PJ, Morrison KE, Farmer AE, Van Damme P, Robberecht W, Chiò A, Traynor BJ, Sendtner M, Melki J, Meininger V, Hardiman O, Andersen PM, Leigh NP, Glass JD, Overste D, Diekstra FP, Veldink JH, van Es MA, Shaw CE, Weale ME, Lewis CM, Williams J, Brown RH, Landers JE, Ticozzi N, Ceroni M, Pegoraro E, Comi GP, D'Alfonso S, van den Berg LH, Taroni F, Al Chalabi A, Powell J, Silani V, SLAGEN Consortium, Collaborators, Among the collaborators, MONSURRO', Maria Rosaria, Fogh, I, Ratti, A, Gellera, C, Lin, K, Tiloca, C, Moskvina, V, Corrado, L, Sorarù, G, Cereda, C, Corti, S, Gentilini, D, Calini, D, Castellotti, B, Mazzini, L, Querin, G, Gagliardi, S, Del Bo, R, Conforti, Fl, Siciliano, G, Inghilleri, M, Saccà, F, Bongioanni, P, Penco, S, Corbo, M, Sorbi, S, Filosto, M, Ferlini, A, Di Blasio, Am, Signorini, S, Shatunov, A, Jones, A, Shaw, Pj, Morrison, Ke, Farmer, Ae, Van Damme, P, Robberecht, W, Chiò, A, Traynor, Bj, Sendtner, M, Melki, J, Meininger, V, Hardiman, O, Andersen, Pm, Leigh, Np, Glass, Jd, Overste, D, Diekstra, Fp, Veldink, Jh, van Es, Ma, Shaw, Ce, Weale, Me, Lewis, Cm, Williams, J, Brown, Rh, Landers, Je, Ticozzi, N, Ceroni, M, Pegoraro, E, Comi, Gp, D'Alfonso, S, van den Berg, Lh, Taroni, F, Al Chalabi, A, Powell, J, Silani, V, Slagen, Consortium, Collaborators, Among the, Collaborator, and Monsurro', Maria Rosaria
- Published
- 2014
7. A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer
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Kiemeney, La, Sulem, P, Besenbacher, S, Vermeulen, Sh, Sigurdsson, A, Thorleifsson, G, Stacey, Sn, Gudmundsson, J, Zanon, C, Kostic, J, Bjarnason, H, Palsson, St, Skarpheoinsson, Ob, Gudjonsson, Sa, Witjes, Ja, Grotenhuis, Aj, Vehaegh, Gw, Bishop, Dt, CHUNG SAK, S, Choudhury, A, Elliott, F, Barrett, Jh, Hurst, Cd, DE VERDIER PK, Rudnai, P, Gurzau, E, Koppova, K, Vineis, P, Polidoro, S, Guarrera, S, Sacerdote, C, Campagna, Marcello, Placidi, Donatella, Arici, Cecilia, Zeegers, Mp, Kellen, E, SAEZ GUTIERREZ, B, SANZ VELEZ JI, SANCHEZ ZALABARDO, M, Valdivia, G, GARCIA PRATS MD, Hengstler, Jg, Blaszkewicz, M, Dietrich, H, Ophoff, Ra, VA DEN BERG LH, Aleiusdottir, K, Kristjansson, K, Geirsson, G, Nikulasson, S, Petursdottir, V, Kong, A, Thorgeirsson, T, Mungan, Na, Lindblom, A, VAN ES MA, Porru, Stefano, Buntinx, F, Golka, K, Mayordomo, Ji, Kumar, R, Matullo, G, Steineck, G, Kiltie, Ae, Aben, Kkh, Jonsson, E, Thorsteinsdottir, U, Knowles, Ma, Rafnar, T, and Stefansson, K.
- Published
- 2010
8. Tau levels do not influence human ALS or motor neuron degeneration in the SOD1G93A mouse.
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Taes I, Goris A, Lemmens R, van Es MA, van den Berg LH, Chio A, Traynor BJ, Birve A, Andersen P, Slowik A, Tomik B, Brown RH Jr, Shaw CE, Al-Chalabi A, Boonen S, Van Den Bosch L, Dubois B, Van Damme P, Robberecht W, and Taes, I
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- 2010
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9. A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS.
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Wills AM, Cronin S, Slowik A, Kasperaviciute D, Van Es MA, Morahan JM, Valdmanis PN, Meininger V, Melki J, Shaw CE, Rouleau GA, Fisher EM, Shaw PJ, Morrison KE, Pamphlett R, Van den Berg LH, Figlewicz DA, Andersen PM, Al-Chalabi A, and Hardiman O
- Published
- 2009
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10. Progranulin genetic variability contributes to amyotrophic lateral sclerosis.
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Sleegers K, Brouwers N, Maurer-Stroh S, van Es MA, Van Damme P, van Vught PWJ, van der Zee J, Serneels S, De Pooter T, Van den Broeck M, Cruts M, Schymkowitz J, De Jonghe P, Rousseau F, van den Berg LH, Robberecht W, and Van Broeckhoven C
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- 2008
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11. Mortality in polytrauma patients with moderate to severe TBI on par with isolated TBI patients: TBI as last frontier in polytrauma patients.
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Niemeyer, MJS, Jochems, D, Houwert, RM, van Es, MA, Leenen, LPH, van Wessem, KJP, Houwert, R M, and van Es, M A
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RETROSPECTIVE studies , *WOUNDS & injuries , *LONGITUDINAL method - Abstract
Background: Mortality caused by Traumatic Brain Injury (TBI) remains high, despite improvements in trauma and critical care. Polytrauma is naturally associated with high mortality. This study compared mortality rates between isolated TBI (ITBI) patients and polytrauma patients with TBI (PTBI) admitted to ICU to investigate if concomitant injuries lead to higher mortality amongst TBI patients.Methods: A 3-year cohort study compared polytrauma patients with TBI (PTBI) with AIS head ≥3 (and AIS of other body regions ≥3) from a prospective collected database to isolated TBI (ITBI) patients from a retrospective collected database with AIS head ≥3 (AIS of other body regions ≤2), both admitted to a single level-I trauma center ICU. Patients <16 years of age, injury caused by asphyxiation, drowning, burns and ICU transfers from and to other hospitals were excluded. Patient demographics, shock and resuscitation parameters, multiple organ dysfunction syndrome (MODS), acute respiratory distress syndrome (ARDS), and mortality data were collected and analyzed for group differences.Results: 259 patients were included; 111 PTBI and 148 ITBI patients. The median age was 54 [33-67] years, 177 (68%) patients were male, median ISS was 26 [20-33]. Seventy-nine (31%) patients died. Patients with PTBI developed more ARDS (7% vs. 1%, p = 0.041) but had similar MODS rates (18% vs. 10%, p = 0.066). They also stayed longer on the ventilator (7 vs. 3 days, p=<0.001), longer in ICU (9 vs. 4 days, p=<0.001) and longer in hospital (24 vs. 11 days, p=<0.001). TBI was the most prevalent cause of death in polytrauma patients. Patients with PTBI showed no higher in-hospital mortality rate. Moreover, mortality rates were skewed towards ITBI patients (24% vs. 35%, p = 0.06).Discussion: There was no difference in mortality rates between PTBI and ITBI patients, suggesting TBI-severity as the predominant factor for ICU mortality in an era of ever improving acute trauma care. [ABSTRACT FROM AUTHOR]- Published
- 2022
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12. Genetic characterization of amyotrophic lateral sclerosis
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Dekker, Annelot Marije, Veldink, Jan Herman, van den Berg, Leonard, Pulit, Sara, van Es, MA, and University Utrecht
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amyotrophic lateral sclerosis ,genetic risk factors ,genetics ,ALS - Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to progressive muscle wasting and weakness, eventually resulting in swallowing difficulties and respiratory failure. There is no cure, and only one drug has been proven irrefutably to increase survival by several months. ALS is considered a complex disease, with both genetic and environmental factors contributing to disease onset, and approximately 5-10% of patients describe a positive family history. This thesis contains multiple studies on the genetic architecture of ALS; ultimately aiming to gain more insight into disease processes and provide a basis for new (personalized) treatments. Using different research methods, we identified new DNA variants (C21orf2, NEK1, MOPB and SCFD1) associated with a higher risk of ALS. Interestingly, the proteins C21OF2 and NEK1 were previously identified as interactors, providing novel insights into ALS disease development. Also, we confirm that the previously identified genetic variant in the gene NIPA1 increases ALS risk, and we show that certain genetic risk factors co-occur more often than expected by chance. This thesis further elucidates the genetic background of ALS, and underlines the importance of future large-scale genetic studies on the disease.
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- 2019
13. Novel risk genes and their clinical impact in amyotrophic lateral sclerosis
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Ticozzi, Nicola, Veldink, Jan Herman, van den Berg, Leonard, van Es, MA, and University Utrecht
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Genetics ,Neurodegeneration ,Amyotrophic lateral sclerosis - Abstract
Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neurodegenerative disease mainly caused by the loss of upper and lower motor neurons, resulting in progressive muscle atrophy and paralysis. Although most ALS cases are sporadic (SALS), ~10% of them are familial (FALS), usually with an autosomal-dominant inheritance pattern. Although genetic studies have partially elucidated the genetic background of the disease, a large part of ALS heritability is still missing. The aim of this thesis was the identification of genetic risk factors in ALS, and to understand their role in shaping the clinical phenotype. To achieve this goal, we initially screened a large cohort of FALS and SALS patients of Italian descent for mutations in the known ALS genes FUS, ATXN2 and PFN1. We established a mutational frequency for FUS of ~5% in familial cases, and described a novel phenotype associated with mutations within the nuclear localization signal of the gene. We confirmed the role of ATXN2 intermediate repeats in SALS susceptibility and refined the CAG-repeat range associated with the disease. We observed that PFN1 mutations are extremely rare in sporadic cases and probably do not play a role in FTD pathogenesis. We then aimed to assess whether mutations in known ALS genes are associated to the appearance of extramotor phenotypes within motor neuron diseases, or contribute to the pathogenesis of neurodegenerative disorders other than ALS and FTD. Our results suggest that rare variants in the ANG gene, previously associated with ALS, also confer a susceptibility to idiopathic Parkinson’s disease (PD). We observed an increased presence of oligoclonal bands in the cerebrospinal fluid (CSF) of ALS patients carrying ANG and TARDBP mutations, suggesting a possible link with inflammatory diseases of the central nervous system. We also confirmed an association of c9orf72 (G4C2)n with ALS-plus syndromes, although we did not find evidence of a pathogenic role in other neurodegenerative disorders beyond TDP-43 protheinopathies. Lastly, we aimed to identify novel causative genes in our ALS cohort, using different methodological approaches. We initially relied upon the candidate gene approach to screen a cohort of unrelated FALS index cases for mutations in TAF15 and EWS, selected because of their homology with FUS, and in the PON cluster, encoding for a family of proteins involved in detoxifying exogenous toxics. Although our results initially suggested an association of TAF15 and PON1-3 with ALS, subsequent evidence has casted significant doubt over these and other genes identified through the candidate gene approach. Faced with these pitfalls, we were forced to adopt a different strategy for gene hunting in ALS, and resorted to an exome-wide, case-control, RVB analysis. The validity of such strategy is highlighted by the identification of the two novel ALS genes TUBA4A and NEK1. Genetic studies in ALS have by far given the largest contribution to our understanding of the pathogenesis of the disease, and it is the hope that further advancements in the field will eventually lead to the identification of therapeutic targets toward finding a cure for ALS.
- Published
- 2017
14. Complexity of familial amyotrophic lateral sclerosis
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van Blitterswijk, M.M., van den Berg, Leonard, Veldink, Jan Herman, van Es, MA, and University Utrecht
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Econometric and Statistical Methods: General ,Bescherming en bevordering van de menselijke gezondheid ,Geneeskunde(GENK) ,Medical sciences ,General [Econometric and Statistical Methods] - Abstract
Each year approximately 400 patients are diagnosed with amyotrophic lateral sclerosis (ALS) in The Netherlands.Thesepatients are ~65 years of age at time of diagnosis.They develop progressive muscleweakness, frequently affecting their arms, legs and trunk, but also muscles involved in speech, swallowing and breathing. ALS patients usually die within three years due to respiratory failure. There is no cure for ALS and only Riluzole prolongs survival with two to three months. The pathogenesis of ALS is complex and involves both genetic and environmentalfactors. In ~5% of the cases more than one family member is affected. These patients are diagnosed with familial ALS (FALS). In the first part of this thesis, we will discuss eleven ALS-associated genes. The next part of this thesis will address other neurodegenerative diseases, including progressive muscular atrophy (PMA) and Parkinson’s disease (PD). Finally, we will describe several functional studies, investigating the effects of genetic abnormalities in ALS-associated genes.
- Published
- 2012
15. ATAXIN-2 intermediate-length polyglutamine expansions elicit ALS-associated metabolic and immune phenotypes.
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Vieira de Sá R, Sudria-Lopez E, Cañizares Luna M, Harschnitz O, van den Heuvel DMA, Kling S, Vonk D, Westeneng HJ, Karst H, Bloemenkamp L, Varderidou-Minasian S, Schlegel DK, Mars M, Broekhoven MH, van Kronenburg NCH, Adolfs Y, Vangoor VR, de Jongh R, Ljubikj T, Peeters L, Seeler S, Mocholi E, Basak O, Gordon D, Giuliani F, Verhoeff T, Korsten G, Calafat Pla T, Venø MT, Kjems J, Talbot K, van Es MA, Veldink JH, van den Berg LH, Zelina P, and Pasterkamp RJ
- Subjects
- Humans, Animals, Mice, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Phenotype, Male, Female, Mitochondria metabolism, Neurites metabolism, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism, Amyotrophic Lateral Sclerosis pathology, Ataxin-2 genetics, Ataxin-2 metabolism, Peptides metabolism, Peptides genetics, Induced Pluripotent Stem Cells metabolism, Motor Neurons metabolism, Motor Neurons pathology, Disease Models, Animal, Mice, Transgenic
- Abstract
Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are the strongest genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. Here, we combine patient-derived and mouse models to dissect the effects of ATXN2 intermediate expansions in an ALS background. iPSC-derived motor neurons from ATXN2-ALS patients show altered stress granules, neurite damage and abnormal electrophysiological properties compared to healthy control and other familial ALS mutations. In TDP-43
Tg -ALS mice, ATXN2-Q33 causes reduced motor function, NMJ alterations, neuron degeneration and altered in vitro stress granule dynamics. Furthermore, gene expression changes related to mitochondrial function and inflammatory response are detected and confirmed at the cellular level in mice and human neuron and organoid models. Together, these results define pathogenic defects underlying ATXN2-ALS and provide a framework for future research into ATXN2-dependent pathogenesis and therapy., (© 2024. The Author(s).)- Published
- 2024
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16. Association Between Hypothalamic Volume and Metabolism, Cognition, and Behavior in Patients With Amyotrophic Lateral Sclerosis.
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Michielsen A, van Veenhuijzen K, Janse van Mantgem MR, van Es MA, Veldink JH, van Eijk RPA, van den Berg LH, and Westeneng HJ
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- Humans, Male, Female, Middle Aged, Aged, Cross-Sectional Studies, Longitudinal Studies, Disease Progression, Cognition physiology, Adult, Energy Metabolism physiology, Amyotrophic Lateral Sclerosis metabolism, Amyotrophic Lateral Sclerosis diagnostic imaging, Amyotrophic Lateral Sclerosis pathology, Hypothalamus diagnostic imaging, Hypothalamus metabolism, Hypothalamus pathology, Magnetic Resonance Imaging
- Abstract
Background and Objectives: Dysfunction of energy metabolism, cognition, and behavior are important nonmotor symptoms of amyotrophic lateral sclerosis (ALS), negatively affecting survival and quality of life, but poorly understood. Neuroimaging is ideally suited to studying nonmotor neurodegeneration in ALS, but few studies have focused on the hypothalamus, a key region for regulating energy homeostasis, cognition, and behavior. We evaluated, therefore, hypothalamic neurodegeneration in ALS and explored the relationship between hypothalamic volumes and dysregulation of energy metabolism, cognitive and behavioral changes, disease progression, and survival., Methods: Patients with ALS and population-based controls were included for this cross-sectional and longitudinal MRI study. The hypothalamus was segmented into 5 subregions and their volumes were calculated. Linear (mixed) models, adjusted for age, sex, and total intracranial volume, were used to compare hypothalamic volumes between groups and to analyze associations with metabolism, cognition, behavior, and disease progression. Cox proportional hazard models were used to investigate the relationship of hypothalamic volumes with survival. Permutation-based corrections for multiple hypothesis testing were applied to all analyses to control the family-wise error rate., Results: Data were available for 564 patients with ALS and 356 controls. The volume of the anterior superior subregion of the hypothalamus was smaller in patients with ALS than in controls (β = -0.70 [-1.15 to -0.25], p = 0.013). Weight loss, memory impairments, and behavioral disinhibition were associated with a smaller posterior hypothalamus (β = -4.79 [-8.39 to -2.49], p = 0.001, β = -10.14 [-15.88 to -4.39], p = 0.004, and β = -12.09 [-18.83 to -5.35], p = 0.003, respectively). Furthermore, the volume of this subregion decreased faster over time in patients than in controls (β = -0.25 [0.42 to -0.09], p = 0.013), and a smaller volume of this structure was correlated with shorter survival (hazard ratio = 0.36 [0.21-0.61], p = 0.029)., Discussion: We obtained evidence for hypothalamic involvement in ALS, specifically marked by atrophy of the anterior superior subregion. Moreover, we found that atrophy of the posterior hypothalamus was associated with weight loss, memory dysfunction, behavioral disinhibition, and survival, and that this subregion deteriorated faster in patients with ALS than in controls. These findings improve our understanding of nonmotor involvement in ALS and could contribute to the identification of new treatment targets for this devastating disease.
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- 2024
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17. Neural stem cell homeostasis is affected in cortical organoids carrying a mutation in Angiogenin.
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Ferguson R, van Es MA, van den Berg LH, and Subramanian V
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- Humans, Mutation, Homeostasis, Amyotrophic Lateral Sclerosis genetics, Frontotemporal Dementia genetics, Frontotemporal Dementia pathology, Neural Stem Cells metabolism, Ribonuclease, Pancreatic
- Abstract
Mutations in Angiogenin (ANG) and TARDBP encoding the 43 kDa transactive response DNA binding protein (TDP-43) are associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). ANG is neuroprotective and plays a role in stem cell dynamics in the haematopoietic system. We obtained skin fibroblasts from members of an ALS-FTD family, one with mutation in ANG, one with mutation in both TARDBP and ANG, and one with neither mutation. We reprogrammed these fibroblasts to induced pluripotent stem cells (iPSCs) and generated cortical organoids as well as induced stage-wise differentiation of the iPSCs to neurons. Using these two approaches we investigated the effects of FTD-associated mutations in ANG and TARDBP on neural precursor cells, neural differentiation, and response to stress. We observed striking neurodevelopmental defects such as abnormal and persistent rosettes in the organoids accompanied by increased self-renewal of neural precursor cells. There was also a propensity for differentiation to later-born neurons. In addition, cortical neurons showed increased susceptibility to stress, which is exacerbated in neurons carrying mutations in both ANG and TARDBP. The cortical organoids and neurons generated from patient-derived iPSCs carrying ANG and TARDBP gene variants recapitulate dysfunctions characteristic of frontotemporal lobar degeneration observed in FTD patients. These dysfunctions were ameliorated upon treatment with wild type ANG. In addition to its well-established role during the stress response of mature neurons, ANG also appears to play a role in neural progenitor dynamics. This has implications for neurogenesis and may indicate that subtle developmental defects play a role in disease susceptibility or onset. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)
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- 2024
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18. 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.
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Van Wijk IF, Van Eijk RPA, Van Boxmeer L, Westeneng HJ, Van Es MA, Van Rheenen W, Van Den Berg LH, Eijkemans MJC, and Veldink JH
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- Humans, Aged, 80 and over, C9orf72 Protein genetics, DNA Repeat Expansion genetics, Proteins genetics, Frontotemporal Dementia genetics, Amyotrophic Lateral Sclerosis epidemiology, Amyotrophic Lateral Sclerosis genetics
- Abstract
Objectives: We aimed to estimate the age-related risk of ALS in first-degree relatives of patients with ALS carrying the C9orf72 repeat expansion., Methods: We included all patients with ALS carrying a C9orf72 repeat expansion in The Netherlands. Using structured questionnaires, we determined the number of first-degree relatives, their age at death due to ALS or another cause, or age at time of questionnaire. The cumulative incidence of ALS among first-degree relatives was estimated, while accounting for death from other causes. Variability in ALS risk between families was evaluated using a random effects hazards model. We used a second, distinct approach to estimate the risk of ALS and FTD in the general population, using previously published data., Results: In total, 214 of the 2,486 (9.2%) patients with ALS carried the C9orf72 repeat expansion. The mean risk of ALS at age 80 for first-degree relatives carrying the repeat expansion was 24.1%, but ranged between individual families from 16.0 to 60.6%. Using the second approach, we found the risk of ALS and FTD combined was 28.7% (95% CI 17.8%-54.3%) for carriers in the general population., Conclusions: On average, our estimated risk of ALS in the C9orf72 repeat expansion was lower compared to historical estimates. We showed, however, that the risk of ALS likely varies between families and one overall penetrance estimate may not be sufficient to describe ALS risk. This warrants a tailor-made, patient-specific approach in testing. Further studies are needed to assess the risk of FTD in the C9orf72 repeat expansion.
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- 2024
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19. Familial motor neuron disease: co-occurrence of PLS and ALS (-FTD).
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de Boer EMJ, Demaegd KC, de Bie CI, Veldink JH, van den Berg LH, and van Es MA
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- Humans, Prospective Studies, Amyotrophic Lateral Sclerosis diagnosis, Amyotrophic Lateral Sclerosis epidemiology, Amyotrophic Lateral Sclerosis genetics, Frontotemporal Dementia genetics, Motor Neuron Disease epidemiology, Motor Neuron Disease genetics, Motor Neuron Disease pathology, Muscular Atrophy, Spinal epidemiology, Muscular Atrophy, Spinal genetics
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Objective: To report the frequency and characteristics of patients diagnosed with primary lateral sclerosis (PLS) with a positive family history for motor neuron diseases (MND) in the Netherlands and to compare our findings to the literature., Methods: Patients were identified through our ongoing, prospective population-based study on MND in The Netherlands, which also includes a standardized collection of patient characteristics, genetic testing, and family history. Only patients meeting the latest consensus criteria for definite PLS were included. The family history was considered positive for MND if any family members had been diagnosed with PLS, amyotrophic lateral sclerosis (ALS)(-FTD), or progressive muscular atrophy (PMA). Additionally, the literature was reviewed on PLS cases in which MND co-occurred within the same family., Results: We identified 392 definite PLS cases, resulting in 9 families with a PLS patient and a positive family history for MND (2.3%). In only one of these pedigrees, a pathogenic variant ( C9orf72 repeat expansion) was found. Our literature review revealed 23 families with a co-occurrence of PLS and MND, with 12 of them having a potentially pathogenic genetic variant., Conclusions: The consistent observation of PLS patients with a positive family history for MND, evident in both our study and the literature, implies the presence of shared underlying genetic factors between PLS and ALS. However, these factors are yet to be elucidated.
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- 2024
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20. Amyotrophic lateral sclerosis; clinical features, differential diagnosis and pathology.
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Van Es MA
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- Humans, Diagnosis, Differential, Frontotemporal Dementia diagnosis, Frontotemporal Dementia genetics, Frontotemporal Dementia physiopathology, Frontotemporal Dementia pathology, Amyotrophic Lateral Sclerosis diagnosis, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis pathology, Amyotrophic Lateral Sclerosis physiopathology
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Amyotrophic lateral sclerosis (ALS) is a late-onset syndrome characterized by the progressive degeneration of both upper motor neurons (UMN) and lower motor neurons (LMN). ALS forms a clinical continuum with frontotemporal dementia (FTD), in which there are progressive language deficits or behavioral changes. The genetics and pathology underlying both ALS and FTD overlap as well, with cytoplasmatic misvocalization of TDP-43 as the hallmark. ALS is diagnosed by exclusion. Over the years several diagnostic criteria have been proposed, which in essence all require a history of slowly progressive motor symptoms, with UMN and LMN signs on neurological examination, clear spread of symptoms through the body, the exclusion of other disorder that cause similar symptoms and an EMG that it is compatible with LMN loss. ALS is heterogeneous disorder that may present in multitude ways, which makes the diagnosis challenging. Therefore, a systematic approach in the diagnostic process is required in line with the most common presentations. Subsequently, assessing whether there are cognitive and/or behavioral changes within the spectrum of FTD and lastly determining the cause is genetic. This chapter, an outline on how to navigate this 3 step process., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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21. Genetic variability in sporadic amyotrophic lateral sclerosis.
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Van Daele SH, Moisse M, van Vugt JJFA, Zwamborn RAJ, van der Spek R, van Rheenen W, Van Eijk K, Kenna K, Corcia P, Vourc'h P, Couratier P, Hardiman O, McLaughin R, Gotkine M, Drory V, Ticozzi N, Silani V, Ratti A, de Carvalho M, Mora Pardina JS, Povedano M, Andersen PM, Weber M, Başak NA, Shaw C, Shaw PJ, Morrison KE, Landers JE, Glass JD, van Es MA, van den Berg LH, Al-Chalabi A, Veldink J, and Van Damme P
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- Humans, United States, Genetic Predisposition to Disease genetics, C9orf72 Protein genetics, Superoxide Dismutase-1 genetics, Amyotrophic Lateral Sclerosis genetics
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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 identified pathogenic and likely pathogenic variants in 11.13% of ALS patients in 38 known ALS genes. In line with the oligogenic hypothesis, we found significantly more combinations of variants in cases compared to controls. Many variants of unknown significance may contribute to ALS risk, but diagnostic algorithms to reliably identify and weigh them are lacking. This work can serve as a resource for counselling and for the assembly of gene panels for ALS. Further characterization of the genetic architecture of sALS is necessary given the growing interest in gene testing in ALS., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2023
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22. Development of a Rasch-Built Amyotrophic Lateral Sclerosis Impairment Multidomain Scale to Measure Disease Progression in ALS.
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de Jongh AD, van Eijk RPA, Bakker LA, Bunte TM, Beelen A, van der Meijden C, van Es MA, Visser-Meily JMA, Kruitwagen ET, Veldink JH, and van den Berg LH
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- Humans, Reproducibility of Results, Prognosis, Probability, Disease Progression, Amyotrophic Lateral Sclerosis
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Background and Objectives: Current scales used in amyotrophic lateral sclerosis (ALS) attempt to summarize different functional domains or "dimensions" into 1 overall score, which may not accurately characterize the individual patient's disease severity or prognosis. The use of composite score risks declaring treatments ineffective if not all dimensions of ALS disease progression are affected equally. We aimed to develop the ALS Impairment Multidomain Scale (AIMS) to comprehensively characterize disease progression and increase the likelihood of identifying effective treatments., Methods: The Revised ALS Functional Rating Scale (ALSFRS-R) and a preliminary questionnaire, based on literature review and patient input, were completed online by patients from the Netherlands ALS registry at bimonthly intervals over a period of 12 months. A 2-week test-retest, factor analysis, Rasch analysis, and a signal-to-noise optimization strategy were performed to create a multidomain scale. Reliability, longitudinal decline, and associations with survival were evaluated. The sample size required to detect a 35% reduction in progression rate over 6 or 12 months was assessed for a clinical trial that defines the ALSFRS-R or AIMS subscales as a primary endpoint family., Results: The preliminary questionnaire, consisting of 110 questions, was completed by 367 patients. Three unidimensional subscales were identified, and a multidomain scale was constructed with 7 bulbar, 11 motor, and 5 respiratory questions. Subscales fulfilled Rasch model requirements, with excellent test-retest reliability of 0.91-0.94 and a strong relationship with survival ( p < 0.001). Compared with the ALSFRS-R, signal-to-noise ratios were higher as patients declined more uniformly per subscale. Consequently, the estimated sample size reductions achieved with the AIMS compared with those achieved with the ALSFRS-R were 16.3% and 25.9% for 6-month and 12-month clinical trials, respectively., Discussion: We developed the AIMS, consisting of unidimensional bulbar, motor, and respiratory subscales, which may characterize disease severity better than a total score. AIMS subscales have high test-retest reliability, are optimized to measure disease progression, and are strongly related to survival time. The AIMS can be easily administered and may increase the likelihood of identifying effective treatments in ALS clinical trials., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2023
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23. Genetic characterization of primary lateral sclerosis.
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de Boer EMJ, de Vries BS, Pennings M, Kamsteeg EJ, Veldink JH, van den Berg LH, and van Es MA
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- Humans, C9orf72 Protein genetics, Motor Neurons pathology, Spastin, Proteins, Flavoproteins, Phosphoric Monoester Hydrolases, Amyotrophic Lateral Sclerosis diagnosis, Frontotemporal Dementia complications, Motor Neuron Disease diagnosis
- Abstract
Background and Objectives: Primary lateral sclerosis (PLS) is a motor neuron disease characterised by loss of the upper motor neurons. Most patients present with slowly progressive spasticity of the legs, which may also spread to the arms or bulbar regions. It is challenging to distinguish between PLS, early-stage amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). The current diagnostic criteria advise against extensive genetic testing. This recommendation is, however, based on limited data., Methods: We aim to genetically characterize a PLS cohort using whole exome sequencing (WES) for genes associated with ALS, HSP, ataxia and movement disorders (364 genes) and C9orf72 repeat expansions. Patients fulfilling the definite PLS criteria by Turner et al. and with available DNA samples of sufficient quality were recruited from an on-going, population-based epidemiological study. Genetic variants were classified according to the ACMG criteria and assigned to groups based on disease association., Results: WES was performed in 139 patients and the presence of repeat expansions in C9orf72 was analysed separately in 129 patients. This resulted in 31 variants of which 11 were (likely) pathogenic. (Likely) pathogenic variants resulted in 3 groups based on disease association: ALS-FTD (C9orf72, TBK1), pure HSP (SPAST, SPG7), "ALS-HSP-CMT overlap" (FIG4, NEFL, SPG11)., Discussion: In a cohort of 139 PLS patients, genetic analyses resulted in 31 variants (22%) of which 10 (7%) (likely) pathogenic associated with different diseases (predominantly ALS and HSP). Based on these results and the literature, we advise to consider genetic analyses in the diagnostic work-up for PLS., (© 2023. The Author(s).)
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- 2023
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24. UNC13A in amyotrophic lateral sclerosis: from genetic association to therapeutic target.
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Willemse SW, Harley P, van Eijk RPA, Demaegd KC, Zelina P, Pasterkamp RJ, van Damme P, Ingre C, van Rheenen W, Veldink JH, Kiernan MC, Al-Chalabi A, van den Berg LH, Fratta P, and van Es MA
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- Humans, Nerve Tissue Proteins genetics, Polymorphism, Genetic, Amyotrophic Lateral Sclerosis drug therapy, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis complications, Frontotemporal Dementia pathology, Neurodegenerative Diseases complications
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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 UNC13A gene 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 UNC13A lead to the inclusion of a cryptic exon in UNC13A messenger RNA, subsequently leading to nonsense mediated decay, with loss of functional protein. Depletion of UNC13A leads to impaired neurotransmission. Recent discoveries have identified UNC13A as a potential target for therapy development in ALS, with a confirmatory trial with lithium carbonate in UNC13A cases now underway and future approaches with antisense oligonucleotides currently under consideration. Considering UNC13A is a potent phenotypic modifier, it may also impact clinical trial outcomes. This present review describes the path from the initial discovery of UNC13A as 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., Competing Interests: Competing interests: PVD has served in advisory boards for Biogen, CSL Behring, Alexion Pharmaceuticals, Ferrer, QurAlis, Cytokinetics, Argenx, UCB, Muna Therapeutics, Alector, Augustine Therapeutics, VectorY (paid to institution). LHvdB declares fees to his institution from Biogen, Wave, Amylyx, Ferrer, and Cytokinetics for being on a scientific advisory board; fees to his institution from Amylyx for a lecture; an unrestricted educational grant from Takeda; and is the Chair of ENCALS and TRICALS. MAvE has consulted for Biogen and has received travel grants from Shire (formerly Baxalta) and serves as medical monitor for Ferrer in the ADORE trial (NCT05178810)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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25. Susceptibility and disease modifier genes in amyotrophic lateral sclerosis: from genetic associations to therapeutic implications.
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Willemse SW and van Es MA
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- Humans, Genes, Modifier, Superoxide Dismutase-1 genetics, Superoxide Dismutase-1 therapeutic use, Motor Neurons, Mutation, Amyotrophic Lateral Sclerosis therapy, Amyotrophic Lateral Sclerosis drug therapy
- Abstract
Purpose of Review: Amyotrophic lateral sclerosis (ALS) is a severe disease characterized by the degeneration of motor neurons. Large-scale genetic studies have now identified over 60 genes that are associated with ALS, which in large part have also been functionally characterized. The purpose of this review is to outline how these advances are being translated into novel therapeutic strategies., Recent Findings: The emergence of techniques that allow the specific therapeutic targeting of a (mutant) gene, in particular antisense oligonucleotide therapy (ASOs), have led to the first successful gene therapy for SOD1-ALS and multiple other gene-targeted trials are underway. This includes genetic variants that modify the disease phenotype as well as causal mutations., Summary: Technological and methodological advances are enabling researchers to unravel the genetics of ALS. Both causal mutations and genetic modifiers are viable therapeutic targets. By performing natural history studies, the phenotype-genotype correlations can be characterized. In conjunction with biomarkers for target engagement and international collaboration, this makes performing gene-targeted trials ALS feasible. The first effective treatment has now been developed for SOD1-ALS and, with multiple studies underway, it seems realistic that more therapies will follow., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2023
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26. Longitudinal Effects of Asymptomatic C9orf72 Carriership on Brain Morphology.
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van Veenhuijzen K, Westeneng HJ, Tan HHG, Nitert AD, van der Burgh HK, Gosselt I, van Es MA, Nijboer TCW, Veldink JH, and van den Berg LH
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- Humans, C9orf72 Protein genetics, Brain pathology, Mutation, Magnetic Resonance Imaging, DNA Repeat Expansion genetics, Amyotrophic Lateral Sclerosis diagnostic imaging, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism, Frontotemporal Dementia genetics
- Abstract
Objective: We investigated effects of C9orf72 repeat expansion and gene expression on longitudinal cerebral changes before symptom onset., Methods: We enrolled 79 asymptomatic family members (AFMs) from 9 families with C9orf72 repeat expansion. Twenty-eight AFMs carried the mutation (C9+). Participants had up to 3 magnetic resonance imaging (MRI) scans, after which we compared motor cortex and motor tracts between C9+ and C9- AFMs using mixed effects models, incorporating kinship to correct for familial relations and lessen effects of other genetic factors. We also compared cortical, subcortical, cerebellar, and connectome structural measurements in a hypothesis-free analysis. We correlated regional C9orf72 expression in donor brains with the pattern of cortical thinning in C9+ AFMs using meta-regression. For comparison, we included 42 C9+ and 439 C9- patients with amyotrophic lateral sclerosis (ALS) in this analysis., Results: C9+ AFM motor cortex had less gyrification and was thinner than in C9- AFMs, without differences in motor tracts. Whole brain analysis revealed thinner cortex and less gyrification in parietal, occipital, and temporal regions, smaller thalami and right hippocampus, and affected frontotemporal connections. Thinning of bilateral precentral, precuneus, and left superior parietal cortex was faster in C9+ than in C9- AFMs. Higher C9orf72 expression correlated with thinner cortex in both C9+ AFMs and C9+ ALS patients., Interpretation: In asymptomatic C9orf72 repeat expansion carriers, brain MRI reveals widespread features suggestive of impaired neurodevelopment, along with faster decline of motor and parietal cortex than found in normal aging. C9orf72 expression might play a role in cortical development, and consequently explain the specific brain abnormalities of mutation carriers. ANN NEUROL 2023;93:668-680., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
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- 2023
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27. Evaluating the influence of alcohol intoxication on the pre-hospital identification of severe head injury: a multi-center, cohort study.
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Lokerman RD, Gulickx M, Waalwijk JF, van Es MA, Tuinema RM, Leenen LPH, and van Heijl M
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- Humans, Cohort Studies, Retrospective Studies, Glasgow Coma Scale, Hospitals, Trauma Centers, Alcoholic Intoxication diagnosis, Craniocerebral Trauma complications, Craniocerebral Trauma diagnosis
- Abstract
Objective: To determine the influence of intoxication on the pre-hospital recognition of severely head-injured patients by Emergency Medical Services (EMS) professionals and to investigate the relationship between suspected alcohol intoxication and severe head injury., Methods: This multi-center, retrospective, cohort study included trauma patients, aged ≥ 16 years, transported by an ambulance of the Regional Ambulance Facility Utrecht to any emergency department in the participating trauma regions., Results: Between January 1, 2015 and December 31, 2017, 19,206 patients were included, of whom 1167 (6.0%) were suspected to have a severe head injury in the field, and 623 (3.2%) were diagnosed with such an injury at the hospital. These injuries were less frequently recognized in patients with a GCS ≥ 13 than in patients with a GCS < 13 (25.0% vs. 76.2%). Patients suspected to be intoxicated had a higher chance to suffer from severe head injury (OR 1.42, 95%-CI 1.22-1.65) and were recognized slightly more often (45.3% vs. 40.2%)., Conclusion: Severe head injuries are difficult to recognize in the field, especially in patients without a decreased GCS. Suspicion of alcohol intoxication did not seem to influence pre-hospital injury recognition, as it possibly makes a severe head injury harder to recognize and simultaneously raises caution for a severe injury.
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- 2023
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28. 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 MR, van Rheenen W, Hackeng AV, van Es MA, Veldink JH, van den Berg LH, and van Eijk RPA
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- Humans, Genome-Wide Association Study, Triglycerides, Cholesterol, HDL, Biomarkers, Amyotrophic Lateral Sclerosis metabolism
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Background and Objective: To explore the association between lipids, polygenic profile scores (PPS) for biomarkers of lipid metabolism, markers of disease severity, and survival in patients with amyotrophic lateral sclerosis (ALS)., Methods: We meta-analyzed the current literature on the prognostic value of lipids in patients with ALS. Subsequently, we evaluated the relationship between lipid levels at diagnosis, clinical disease stage, and survival in all consecutive patients diagnosed in the Netherlands. We determined the hazard ratio (HR) of each lipid for overall survival, defined as death from any cause. A subset of patients was matched to a previous genome-wide association study; data were used to calculate PPS for biomarkers of lipid metabolism and to determine the association between observed lipid levels at diagnosis and survival., Results: Meta-analysis of 4 studies indicated that none of the biomarkers of the lipid metabolism were statistically significantly associated with overall survival; there was, however, considerable heterogeneity between study results. Using individual patient data (N = 1,324), we found that increased high-density lipoprotein (HDL) cholesterol was associated with poorer survival (HR of 1.33 (95% CI 1.14-1.55, p < 0.001)). The correlation between BMI and HDL cholesterol (Pearson r -0.26, 95% CI -0.32 to -0.20) was negative and between BMI and triglycerides (TG) positive (Pearson r 0.18, 95% CI 0.12-0.24). Serum concentrations of total cholesterol and LDL cholesterol were lower in more advanced clinical stages (both p < 0.001). PPS for biomarkers of lipid metabolism explained 1.2%-13.1% of their variance at diagnosis. None of the PPS was significantly associated with survival (all p > 0.50)., Discussion: Lipids may contain valuable information about disease severity and prognosis, but their main value may be driven as a consequence of disease progression. Our results underscore that gaining further insight into lipid metabolism and longitudinal data on serum concentrations of the lipid profile could improve the monitoring of patients and potentially further disentangle ALS pathogenesis., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2023
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29. Whole genome sequencing analysis reveals post-zygotic mutation variability in monozygotic twins discordant for amyotrophic lateral sclerosis.
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Tazelaar GHP, Hop PJ, Seelen M, van Vugt JJFA, van Rheenen W, Kool L, van Eijk KR, Gijzen M, Dooijes D, Moisse M, Calvo A, Moglia C, Brunetti M, Canosa A, Nordin A, Pardina JSM, Ravits J, Al-Chalabi A, Chio A, McLaughlin RL, Hardiman O, Van Damme P, de Carvalho M, Neuwirth C, Weber M, Andersen PM, van den Berg LH, Veldink JH, and van Es MA
- Subjects
- Humans, Twins, Monozygotic genetics, Mutation genetics, Whole Genome Sequencing, Amyotrophic Lateral Sclerosis genetics, Neurodegenerative Diseases
- 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., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2023
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30. Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data.
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Al Khleifat A, Iacoangeli A, Jones AR, van Vugt JJFA, Moisse M, Shatunov A, Zwamborn RAJ, van der Spek RAA, Cooper-Knock J, Topp S, van Rheenen W, Kenna B, Van Eijk KR, Kenna K, Byrne R, López V, Opie-Martin S, Vural A, Campos Y, Weber M, Smith B, Fogh I, Silani V, Morrison KE, Dobson R, van Es MA, McLaughlin RL, Vourc'h P, Chio A, Corcia P, de Carvalho M, Gotkine M, Panades MP, Mora JS, Shaw PJ, Landers JE, Glass JD, Shaw CE, Basak N, Hardiman O, Robberecht W, Van Damme P, van den Berg LH, Veldink JH, and Al-Chalabi A
- 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 in telomere length between sporadic ALS and familial ALS (p=0.64), telomere length in 334 people with ALS due to expanded C9orf72 repeats was shorter than in those without expanded C9orf72 repeats (p = 5.0×10-4 )., Discussion: Although telomeres shorten with age, longer telomeres are a risk factor for ALS and worsen prognosis. Longer telomeres are associated with ALS., Competing Interests: AA-C was a consultant for Mitsubishi-Tanabe Pharma, GSK, and Chronos Therapeutics, and chief investigator for clinical trials for Cytokinetics and OrionPharma. JvV reports to have sponsored research agreements with Biogen. VS was a consultant for Novartis and Biogen. LB reports grants from Netherlands ALS Foundation, grants from Netherlands Organization for Health Research and Development (Vici Scheme), grants from The European Community’s Health Seventh Framework Programme [grant agreement no. 259867 (EuroMOTOR)], grants from 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; personal fees from Calico, personal fees from Cytokinetics, grants and personal fees from Takeda, non-financial support from Orion, non-financial support from Orphazyme, outside the submitted work. AA-C also serves on scientific advisory boards for Mitsubishi Tanabe, Roche, Denali Pharma, Cytokinetics, Lilly, and Amylyx research. CS reports grants from Avexis, grants from Eli Lilly, grants from Chronos Therapeutics, grants from Vertex Pharmaceuticals, during the conduct of the study; grants from QurAlis, grants from Chronos Therapeutics, grants from Biogen, outside the submitted work. JL was a member of the scientific advisory board for Cerevel Therapeutics, a consultant for ACI Clinical LLC sponsored by Biogen, Inc. or Ionis Pharmaceuticals, Inc. JL was also a consultant for Perkins Coie LLP and may provide expert testimony and also supported by funding from NIH/NINDS (R01NS073873 and R56NS073873). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Al Khleifat, Iacoangeli, Jones, van Vugt, Moisse, Shatunov, Zwamborn, van der Spek, Cooper-Knock, Topp, van Rheenen, Kenna, Van Eijk, Kenna, Byrne, López, Opie-Martin, Vural, Campos, Weber, Smith, Fogh, Silani, Morrison, Dobson, van Es, McLaughlin, Vourc’h, Chio, Corcia, de Carvalho, Gotkine, Panades, Mora, Shaw, Landers, Glass, Shaw, Basak, Hardiman, Robberecht, Van Damme, van den Berg, Veldink and Al-Chalabi.)- Published
- 2022
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31. 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.
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Willemse SW, Roes KCB, Van Damme P, Hardiman O, Ingre C, Povedano M, Wray NR, Gijzen M, de Pagter MS, Demaegd KC, Janse AFC, Vink RG, Sleutjes BTHM, Chiò A, Corcia P, Reviers E, Al-Chalabi A, Kiernan MC, van den Berg LH, van Es MA, and van Eijk RPA
- Subjects
- Humans, Lithium Carbonate adverse effects, Polymorphism, Single Nucleotide, Alleles, Quality of Life, Randomized Controlled Trials as Topic, Meta-Analysis as Topic, Amyotrophic Lateral Sclerosis diagnosis, Amyotrophic Lateral Sclerosis drug therapy, Amyotrophic Lateral Sclerosis genetics, Respiratory Insufficiency drug therapy
- Abstract
Background: Given the large genetic heterogeneity in amyotrophic lateral sclerosis (ALS), it seems likely that genetic subgroups may benefit differently from treatment. An exploratory meta-analysis identified that patients homozygous for the C-allele at SNP rs12608932, a single nucleotide polymorphism in the gene UNC13A, had a statistically significant survival benefit when treated with lithium carbonate. We aim to confirm the efficacy of lithium carbonate on the time to death or respiratory insufficiency in patients with ALS homozygous for the C-allele at SNP rs12608932 in UNC13A., Methods: A randomized, group-sequential, event-driven, double-blind, placebo-controlled trial will be conducted in 15 sites across Europe and Australia. Patients will be genotyped for UNC13A; those homozygous for the C-allele at SNP rs12608932 will be eligible. Patients must have a diagnosis of ALS according to the revised El Escorial criteria, and a TRICALS risk-profile score between -6.0 and -2.0. An expected number of 1200 patients will be screened in order to enroll a target sample size of 171 patients. Patients will be randomly allocated in a 2:1 ratio to lithium carbonate or matching placebo, and treated for a maximum duration of 24 months. The primary endpoint is the time to death or respiratory insufficiency, whichever occurs first. Key secondary endpoints include functional decline, respiratory function, quality of life, tolerability, and safety. An interim analysis for futility and efficacy will be conducted after the occurrence of 41 events., Discussion: Lithium carbonate has been proven to be safe and well-tolerated in patients with ALS. Given the favorable safety profile, the potential benefits are considered to outweigh the burden and risks associated with study participation. This study may provide conclusive evidence about the life-prolonging potential of lithium carbonate in a genetic ALS subgroup., Trial Registration: EudraCT number 2020-000579-19 . Registered on 29 March 2021., (© 2022. The Author(s).)
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- 2022
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32. MRI Clustering Reveals Three ALS Subtypes With Unique Neurodegeneration Patterns.
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Tan HHG, Westeneng HJ, Nitert AD, van Veenhuijzen K, Meier JM, van der Burgh HK, van Zandvoort MJE, van Es MA, Veldink JH, and van den Berg LH
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- Male, Female, Humans, Diffusion Tensor Imaging, Magnetic Resonance Imaging, Cluster Analysis, Amyotrophic Lateral Sclerosis genetics, Frontotemporal Dementia pathology
- Abstract
Objective: The purpose of this study was to identify subtypes of amyotrophic lateral sclerosis (ALS) by comparing patterns of neurodegeneration using brain magnetic resonance imaging (MRI) and explore their phenotypes., Methods: We performed T1-weighted and diffusion tensor imaging in 488 clinically well-characterized patients with ALS and 338 control subjects. Measurements of whole-brain cortical thickness and white matter connectome fractional anisotropy were adjusted for disease-unrelated variation. A probabilistic network-based clustering algorithm was used to divide patients into subgroups of similar neurodegeneration patterns. Clinical characteristics and cognitive profiles were assessed for each subgroup. In total, 512 follow-up scans were used to validate clustering results longitudinally., Results: The clustering algorithm divided patients with ALS into 3 subgroups of 187, 163, and 138 patients. All subgroups displayed involvement of the precentral gyrus and are characterized, respectively, by (1) pure motor involvement (pure motor cluster [PM]), (2) orbitofrontal and temporal involvement (frontotemporal cluster [FT]), and (3) involvement of the posterior cingulate cortex, parietal white matter, temporal operculum, and cerebellum (cingulate-parietal-temporal cluster [CPT]). These subgroups had significantly distinct clinical profiles regarding male-to-female ratio, age at symptom onset, and frequency of bulbar symptom onset. FT and CPT revealed higher rates of cognitive impairment on the Edinburgh cognitive and behavioral ALS screen (ECAS). Longitudinally, clustering remained stable: at 90.4% of their follow-up visits, patients clustered in the same subgroup as their baseline visit., Interpretation: ALS can manifest itself in 3 main patterns of cerebral neurodegeneration, each associated with distinct clinical characteristics and cognitive profiles. Besides the pure motor and frontotemporal dementia (FTD)-like variants of ALS, a new neuroimaging phenotype has emerged, characterized by posterior cingulate, parietal, temporal, and cerebellar involvement. ANN NEUROL 2022;92:1030-1045., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
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- 2022
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33. Rhabdomyolysis after COVID-19 Comirnaty Vaccination: A Case Report.
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Ruijters VJ, van der Meulen MFG, van Es MA, Smit T, and Hoogendijk JE
- Abstract
Rhabdomyolysis is an acute disruption in skeletal muscle integrity, leading to the rapid release of 4 muscle contents into the bloodstream, such as creatine kinase (CK). It can have various causes, including infections. Throughout the pandemic, multiple cases of rhabdomyolysis following COVID-19 infections have been reported. However, rhabdomyolysis subsequent to COVID-19 vaccinations appears to be relatively rare. Here, we report such a case after a second COVID-19 Comirnaty (BioNTech/Pfizer) vaccination. Our patient developed rhabdomyolysis 1 day after the second Comirnaty vaccination with high creatine kinase (CK) levels, generalized weakness, and kidney failure. CK levels and muscle weakness resolved after treatment with intravenous fluids, but unfortunately, he remained hemodialysis dependent after discharge. To our knowledge, this is one of the first case reports describing a patient with rhabdomyolysis after a Comirnaty vaccination. However, as millions of people have received the Comirnaty vaccine, it is unclear whether the rhabdomyolysis in our patient is a rare side effect or an unrelated, coincidental event. Large observational studies are needed to elucidate the causality between the Comirnaty vaccination and rhabdomyolysis. Awareness is warranted in patients with myalgia and muscle weakness shortly after COVID-19 vaccination, in order to initiate treatment early and prevent life-threatening complications., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)
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- 2022
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34. Clinical trials in pediatric ALS: a TRICALS feasibility study.
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Kliest T, Van Eijk RPA, Al-Chalabi A, Albanese A, Andersen PM, Amador MDM, BrÅthen G, Brunaud-Danel V, Brylev L, Camu W, De Carvalho M, Cereda C, Cetin H, Chaverri D, Chiò A, Corcia P, Couratier P, De Marchi F, Desnuelle C, Van Es MA, Esteban J, Filosto M, GarcÍa Redondo A, Grosskreutz J, Hanemann CO, HolmØy T, HØyer H, Ingre C, Koritnik B, Kuzma-Kozakiewicz M, Lambert T, Leigh PN, Lunetta C, Mandrioli J, Mcdermott CJ, Meyer T, Mora JS, Petri S, Povedano M, Reviers E, Riva N, Roes KCB, Rubio MÁ, Salachas F, Sarafov S, SorarÙ G, Stevic Z, Svenstrup K, MØller AT, Turner MR, Van Damme P, Van Leeuwen LAG, Varona L, VÁzquez Costa JF, Weber M, Hardiman O, and Van Den Berg LH
- Subjects
- Adult, Child, Humans, Feasibility Studies, Europe, Databases, Factual, Prevalence, Amyotrophic Lateral Sclerosis diagnosis, Amyotrophic Lateral Sclerosis epidemiology, Amyotrophic Lateral Sclerosis therapy
- 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.
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- 2022
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35. Characterising ALS disease progression according to El Escorial and Gold Coast criteria.
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de Jongh AD, Braun N, Weber M, van Es MA, Masrori P, Veldink JH, van Damme P, van den Berg LH, and van Eijk RPA
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- Humans, Belgium epidemiology, Disease Progression, Netherlands, Amyotrophic Lateral Sclerosis
- Abstract
Background: The 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., Methods: Data 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., Results: We 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)., Conclusions: The 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., Competing Interests: Competing interests: ADdJ, MW, NB, MAvE, PM, JHV, LHvdB and RPAvE report no disclosures relevant to this study. PvD 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'. Several authors of this publication are member of the European Reference Network for Rare Neuromuscular Diseases (ERN-NMD)., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
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36. Distal spinal muscular atrophy featured by predominant calf muscle involvement in VRK1 associated disease - Case series and review.
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Demaegd K, Brilstra EH, Hoogendijk JE, de Bie CI, de Pagter MS, van Hecke W, Mühlebner A, van Es MA, Milone M, and van Rheenen W
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- Humans, Intracellular Signaling Peptides and Proteins, Muscle, Skeletal diagnostic imaging, Muscular Atrophy, Pedigree, Protein Serine-Threonine Kinases, Leg, Muscular Atrophy, Spinal genetics
- Abstract
We describe the shared clinical, biochemical, radiological and myopathological characteristics of four patients with distal spinal muscular atrophy (dSMA) caused by vaccinia-related kinase 1 (VRK1) variants and provide a review of the literature on phenotype-genotype correlations in VRK1-related disease. The clinical phenotype was characterized by adult-onset dSMA with predominant calf muscle involvement and mildly elevated serum creatinine kinase (CK) levels. Muscle imaging showed predominant atrophy and fatty replacement of calf muscles. We identified the novel compound heterozygous variants c.607C>T (p.Arg203Trp) and c.858G>T (p.Met286Ile) in two siblings with adult-onset dSMA. Additionally, two unrelated patients both carried the known c.583T>G (p.Leu195Val) VRK1 variant, with either c.197C>G (p.Ala66Gly) or c.701A>G (p.Asn234Ser) as a second variant. We conclude that compound heterozygous VRK1 variants cause distal spinal muscular atrophy with predominant posterior leg muscle involvement., Competing Interests: Declarations of interest Margherita Milone reports Research funding from the Neurology Department and CCaTS-CBD Pilot Awards for Team Science, Mayo Clinic; a Muscular Dystrophy Association Care center grant (MDA 497263), and honorarium to serve as associate editor for Neurology Genetics., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2022
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37. 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 W, van der Spek RAA, Bakker MK, van Vugt JJFA, Hop PJ, Zwamborn RAJ, de Klein N, Westra HJ, Bakker OB, Deelen P, Shireby G, Hannon E, Moisse M, Baird D, Restuadi R, Dolzhenko E, Dekker AM, Gawor K, Westeneng HJ, Tazelaar GHP, van Eijk KR, Kooyman M, Byrne RP, Doherty M, Heverin M, Al Khleifat A, Iacoangeli A, Shatunov A, Ticozzi N, Cooper-Knock J, Smith BN, Gromicho M, Chandran S, Pal S, Morrison KE, Shaw PJ, Hardy J, Orrell RW, Sendtner M, Meyer T, Başak N, van der Kooi AJ, Ratti A, Fogh I, Gellera C, Lauria G, Corti S, Cereda C, Sproviero D, D'Alfonso S, Sorarù G, Siciliano G, Filosto M, Padovani A, Chiò A, Calvo A, Moglia C, Brunetti M, Canosa A, Grassano M, Beghi E, Pupillo E, Logroscino G, Nefussy B, Osmanovic A, Nordin A, Lerner Y, Zabari M, Gotkine M, Baloh RH, Bell S, Vourc'h P, Corcia P, Couratier P, Millecamps S, Meininger V, Salachas F, Mora Pardina JS, Assialioui A, Rojas-García R, Dion PA, Ross JP, Ludolph AC, Weishaupt JH, Brenner D, Freischmidt A, Bensimon G, Brice A, Durr A, Payan CAM, Saker-Delye S, Wood NW, Topp S, Rademakers R, Tittmann L, Lieb W, Franke A, Ripke S, Braun A, Kraft J, Whiteman DC, Olsen CM, Uitterlinden AG, Hofman A, Rietschel M, Cichon S, Nöthen MM, Amouyel P, Traynor BJ, Singleton AB, Mitne Neto M, Cauchi RJ, Ophoff RA, Wiedau-Pazos M, Lomen-Hoerth C, van Deerlin VM, Grosskreutz J, Roediger A, Gaur N, Jörk A, Barthel T, Theele E, Ilse B, Stubendorff B, Witte OW, Steinbach R, Hübner CA, Graff C, Brylev L, Fominykh V, Demeshonok V, Ataulina A, Rogelj B, Koritnik B, Zidar J, Ravnik-Glavač M, Glavač D, Stević Z, Drory V, Povedano M, Blair IP, Kiernan MC, Benyamin B, Henderson RD, Furlong S, Mathers S, McCombe PA, Needham M, Ngo ST, Nicholson GA, Pamphlett R, Rowe DB, Steyn FJ, Williams KL, Mather KA, Sachdev PS, Henders AK, Wallace L, de Carvalho M, Pinto S, Petri S, Weber M, Rouleau GA, Silani V, Curtis CJ, Breen G, Glass JD, Brown RH Jr, Landers JE, Shaw CE, Andersen PM, Groen EJN, van Es MA, Pasterkamp RJ, Fan D, Garton FC, McRae AF, Davey Smith G, Gaunt TR, Eberle MA, Mill J, McLaughlin RL, Hardiman O, Kenna KP, Wray NR, Tsai E, Runz H, Franke L, Al-Chalabi A, Van Damme P, van den Berg LH, and Veldink JH
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- 2022
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38. Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS.
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Hop PJ, Zwamborn RAJ, Hannon E, Shireby GL, Nabais MF, Walker EM, van Rheenen W, van Vugt JJFA, Dekker AM, Westeneng HJ, Tazelaar GHP, van Eijk KR, Moisse M, Baird D, Al Khleifat A, Iacoangeli A, Ticozzi N, Ratti A, Cooper-Knock J, Morrison KE, Shaw PJ, Basak AN, Chiò A, Calvo A, Moglia C, Canosa A, Brunetti M, Grassano M, Gotkine M, Lerner Y, Zabari M, Vourc'h P, Corcia P, Couratier P, Mora Pardina JS, Salas T, Dion P, Ross JP, Henderson RD, Mathers S, McCombe PA, Needham M, Nicholson G, Rowe DB, Pamphlett R, Mather KA, Sachdev PS, Furlong S, Garton FC, Henders AK, Lin T, Ngo ST, Steyn FJ, Wallace L, Williams KL, Neto MM, Cauchi RJ, Blair IP, Kiernan MC, Drory V, Povedano M, de Carvalho M, Pinto S, Weber M, Rouleau GA, Silani V, Landers JE, Shaw CE, Andersen PM, McRae AF, van Es MA, Pasterkamp RJ, Wray NR, McLaughlin RL, Hardiman O, Kenna KP, Tsai E, Runz H, Al-Chalabi A, van den Berg LH, Van Damme P, Mill J, and Veldink JH
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- Cholesterol, DNA Methylation genetics, Epigenesis, Genetic, Genome-Wide Association Study, Humans, Amyotrophic Lateral Sclerosis genetics, Neurodegenerative Diseases genetics
- 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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39. Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis.
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Al Khleifat A, Iacoangeli A, van Vugt JJFA, Bowles H, Moisse M, Zwamborn RAJ, van der Spek RAA, Shatunov A, Cooper-Knock J, Topp S, Byrne R, Gellera C, López V, Jones AR, Opie-Martin S, Vural A, Campos Y, van Rheenen W, Kenna B, Van Eijk KR, Kenna K, Weber M, Smith B, Fogh I, Silani V, Morrison KE, Dobson R, van Es MA, McLaughlin RL, Vourc'h P, Chio A, Corcia P, de Carvalho M, Gotkine M, Panades MP, Mora JS, Shaw PJ, Landers JE, Glass JD, Shaw CE, Basak N, Hardiman O, Robberecht W, Van Damme P, van den Berg LH, Veldink JH, and Al-Chalabi A
- Abstract
There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the C9orf72 gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the VCP gene and insertion in the ERBB4 gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured ERBB4 insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype., (© 2022. The Author(s).)
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- 2022
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40. Cortical and subcortical changes in resting-state neuronal activity and connectivity in early symptomatic ALS and advanced frontotemporal dementia.
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Govaarts R, Beeldman E, Fraschini M, Griffa A, Engels MMA, van Es MA, Veldink JH, van den Berg LH, van der Kooi AJ, Pijnenburg YAL, de Visser M, Stam CJ, Raaphorst J, and Hillebrand A
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- Brain diagnostic imaging, Brain Mapping, Cross-Sectional Studies, Humans, Magnetic Resonance Imaging, Amyotrophic Lateral Sclerosis diagnostic imaging, Frontotemporal Dementia diagnostic imaging
- Abstract
The objective of this study was to examine if patterns of resting-state brain activity and functional connectivity in cortical and subcortical regions in patients with early symptomatic amyotrophic lateral sclerosis (ALS) resemble those of behavioural variant frontotemporal dementia (bvFTD). In a cross-sectional design, eyes-closed resting-state magnetoencephalography (MEG) data of 34 ALS patients, 18 bvFTD patients and 18 age- and gender-matched healthy controls (HCs) were projected to source-space using an atlas-based beamformer. Group differences in peak frequency, band-specific oscillatory activity and functional connectivity (corrected amplitude envelope correlation) in 78 cortical regions and 12 subcortical regions were determined. False discovery rate was used to correct for multiple comparisons. BvFTD patients, as compared to ALS and HCs, showed lower relative beta power in parietal, occipital, temporal and nearly all subcortical regions. Compared to HCs, patients with ALS and patients with bvFTD had a higher delta (0.5-4 Hz) and gamma (30-48 Hz) band resting-state functional connectivity in a high number of overlapping regions in the frontal lobe and in limbic and subcortical regions. Higher delta band connectivity was widespread in the bvFTD patients compared to HCs. ALS showed a more widespread higher gamma band functional connectivity compared to bvFTD. In conclusion, MEG in early symptomatic ALS patients shows resting-state functional connectivity changes in frontal, limbic and subcortical regions that overlap considerably with bvFTD. The findings show the potential of MEG to detect brain changes in early symptomatic phases of ALS and contribute to our understanding of the disease spectrum, with ALS and bvFTD at the two extreme ends., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2022
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41. Sensitivity of brain MRI and neurological examination for detection of upper motor neurone degeneration in amyotrophic lateral sclerosis.
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Nitert AD, Tan HH, Walhout R, Knijnenburg NL, van Es MA, Veldink JH, Hendrikse J, Westeneng HJ, and van den Berg LH
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- Biomarkers, Case-Control Studies, Female, Humans, Male, Netherlands, Neuroimaging, Neurologic Examination, Pyramidal Tracts diagnostic imaging, Amyotrophic Lateral Sclerosis diagnostic imaging, Magnetic Resonance Imaging, Motor Cortex diagnostic imaging, Motor Neurons pathology
- Abstract
Objectives: To investigate sensitivity of brain MRI and neurological examination for detection of upper motor neuron (UMN) degeneration in patients with amyotrophic lateral sclerosis (ALS)., Methods: We 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., Results: We 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., Conclusions: Motor 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., Competing Interests: Competing interests: LHvdB received travel grants and consultancy fees from Shire and serves on scientific advisory boards for Treeway, Cytokinetics, and Biogen, outside the submitted work. MAvE serves on the medical ethical review board of the UMC Utrecht and received travel grants from Shire and has consulted for Biogen, outside the submitted work. JHV reports having sponsored research agreements with Biogen, outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)- Published
- 2022
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42. 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 W, van der Spek RAA, Bakker MK, van Vugt JJFA, Hop PJ, Zwamborn RAJ, de Klein N, Westra HJ, Bakker OB, Deelen P, Shireby G, Hannon E, Moisse M, Baird D, Restuadi R, Dolzhenko E, Dekker AM, Gawor K, Westeneng HJ, Tazelaar GHP, van Eijk KR, Kooyman M, Byrne RP, Doherty M, Heverin M, Al Khleifat A, Iacoangeli A, Shatunov A, Ticozzi N, Cooper-Knock J, Smith BN, Gromicho M, Chandran S, Pal S, Morrison KE, Shaw PJ, Hardy J, Orrell RW, Sendtner M, Meyer T, Başak N, van der Kooi AJ, Ratti A, Fogh I, Gellera C, Lauria G, Corti S, Cereda C, Sproviero D, D'Alfonso S, Sorarù G, Siciliano G, Filosto M, Padovani A, Chiò A, Calvo A, Moglia C, Brunetti M, Canosa A, Grassano M, Beghi E, Pupillo E, Logroscino G, Nefussy B, Osmanovic A, Nordin A, Lerner Y, Zabari M, Gotkine M, Baloh RH, Bell S, Vourc'h P, Corcia P, Couratier P, Millecamps S, Meininger V, Salachas F, Mora Pardina JS, Assialioui A, Rojas-García R, Dion PA, Ross JP, Ludolph AC, Weishaupt JH, Brenner D, Freischmidt A, Bensimon G, Brice A, Durr A, Payan CAM, Saker-Delye S, Wood NW, Topp S, Rademakers R, Tittmann L, Lieb W, Franke A, Ripke S, Braun A, Kraft J, Whiteman DC, Olsen CM, Uitterlinden AG, Hofman A, Rietschel M, Cichon S, Nöthen MM, Amouyel P, Traynor BJ, Singleton AB, Mitne Neto M, Cauchi RJ, Ophoff RA, Wiedau-Pazos M, Lomen-Hoerth C, van Deerlin VM, Grosskreutz J, Roediger A, Gaur N, Jörk A, Barthel T, Theele E, Ilse B, Stubendorff B, Witte OW, Steinbach R, Hübner CA, Graff C, Brylev L, Fominykh V, Demeshonok V, Ataulina A, Rogelj B, Koritnik B, Zidar J, Ravnik-Glavač M, Glavač D, Stević Z, Drory V, Povedano M, Blair IP, Kiernan MC, Benyamin B, Henderson RD, Furlong S, Mathers S, McCombe PA, Needham M, Ngo ST, Nicholson GA, Pamphlett R, Rowe DB, Steyn FJ, Williams KL, Mather KA, Sachdev PS, Henders AK, Wallace L, de Carvalho M, Pinto S, Petri S, Weber M, Rouleau GA, Silani V, Curtis CJ, Breen G, Glass JD, Brown RH Jr, Landers JE, Shaw CE, Andersen PM, Groen EJN, van Es MA, Pasterkamp RJ, Fan D, Garton FC, McRae AF, Davey Smith G, Gaunt TR, Eberle MA, Mill J, McLaughlin RL, Hardiman O, Kenna KP, Wray NR, Tsai E, Runz H, Franke L, Al-Chalabi A, Van Damme P, van den Berg LH, and Veldink JH
- Subjects
- Amyotrophic Lateral Sclerosis metabolism, Brain metabolism, Cholesterol blood, Disease Progression, Female, Glutamine metabolism, Humans, Male, Mendelian Randomization Analysis, Microsatellite Repeats, Neurodegenerative Diseases genetics, Quantitative Trait Loci, RNA-Seq, Risk Factors, Amyotrophic Lateral Sclerosis genetics, Genome-Wide Association Study, Mutation, Neurons metabolism
- Abstract
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., (© 2021. The Author(s).)
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- 2021
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43. Discussing Personalized Prognosis Empowers Patients with Amyotrophic Lateral Sclerosis to Regain Control over Their Future: A Qualitative Study.
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van Eenennaam RM, Koppenol LS, Kruithof WJ, Kruitwagen-van Reenen ET, Pieters S, van Es MA, van den Berg LH, Visser-Meily JMA, and Beelen A
- Abstract
The ENCALS survival prediction model offers patients with amyotrophic lateral sclerosis (ALS) the opportunity to receive a personalized prognosis of survival at the time of diagnosis. We explored experiences of patients with ALS, caregivers, and physicians with discussing personalized prognosis through interviews with patients and their caregivers, and in a focus group of physicians. Thematic analysis revealed four themes with seven subthemes; these were recognized by the focus group. First, tailored communication: physician's communication style and information provision mediated emotional impact and increased satisfaction with communication. Second, personal factors: coping style, illness experiences, and information needs affected patient and caregiver coping with the prognosis. Third, emotional impact ranged from happy and reassuring to regret. Fourth, regaining control over the future: participants found it helpful in looking towards the future, and emphasized the importance of quality over quantity of life. Personalized prognosis can be discussed with minimal adverse emotional impact. How it is communicated-i.e., tailored to individual needs-is as important as what is communicated-i.e., a good or poor prognosis. Discussing personalized prognosis may help patients with ALS and their caregivers regain control over the future and facilitate planning of the future (care). For many patients, quality of life matters more than quantity of time remaining.
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- 2021
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44. Genotype-phenotype correlations of KIF5A stalk domain variants.
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de Boer EMJ, van Rheenen W, Goedee HS, Kamsteeg EJ, Brilstra EH, Veldink JH, van Den Berg LH, and van Es MA
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- Adolescent, Child, Genetic Association Studies, Humans, Kinesins genetics, Mutation genetics, Phenotype, Young Adult, Amyotrophic Lateral Sclerosis, Spastic Paraplegia, Hereditary genetics
- Abstract
The kinesin family member 5A ( KIF5A ) motor domain variants are typically associated with hereditary spastic paraplegia (HSP) or Charcot-Marie-Tooth 2 ( CMT2 ), while KIF5A tail variants predispose to amyotrophic lateral sclerosis (ALS) and neonatal intractable myoclonus. Variants within the stalk domain of KIF5A are relatively rare. We describe a family of three patients with a complex HSP phenotype and a likely pathogenic KIF5A stalk variant. More family members were reported to have walking difficulties. When reviewing the literature on KIF5A stalk variants, we found 22 other cases. The phenotypes varied with most cases having (complex) HSP/CMT2 or ALS. Symptom onset varied from childhood to adulthood and common additional symptoms for HSP are involvement of the upper limbs, sensorimotor polyneuropathy, and foot deformities. We conclude that KIF5A variants lead to a broad clinical spectrum of disease. Phenotype distribution according to variants in specific domains occurs often in the motor and tail domain but are not definite. However, variants in the stalk domain are not bound to a specific phenotype.
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- 2021
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45. Epidemiology of paediatric moderate and severe traumatic brain injury in the Netherlands.
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Jochems D, van Rein E, Niemeijer M, van Heijl M, van Es MA, Nijboer T, Leenen LPH, Houwert RM, and van Wessem KJP
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- Adolescent, Child, Child, Preschool, Hospitalization, Humans, Incidence, Netherlands epidemiology, Retrospective Studies, Brain Injuries, Traumatic epidemiology
- 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 <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., Conclusion: 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., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2021
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46. Incidence, causes and consequences of moderate and severe traumatic brain injury as determined by Abbreviated Injury Score in the Netherlands.
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Jochems D, van Rein E, Niemeijer M, van Heijl M, van Es MA, Nijboer T, Leenen LPH, Houwert RM, and van Wessem KJP
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- Accidental Falls statistics & numerical data, Accidents, Traffic statistics & numerical data, Aged, Aged, 80 and over, Brain Injuries, Traumatic mortality, Cohort Studies, Female, Hospitalization, Humans, Incidence, Injury Severity Score, Male, Middle Aged, Multiple Trauma epidemiology, Multiple Trauma etiology, Multiple Trauma mortality, Netherlands epidemiology, Retrospective Studies, Brain Injuries, Traumatic epidemiology, Brain Injuries, Traumatic etiology
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Traumatic brain injury (TBI) is a leading cause of death and disability. Epidemiology seems to be changing. TBIs are increasingly caused by falls amongst elderly, whilst we see less polytrauma due to road traffic accidents (RTA). Data on epidemiology is essential to target prevention strategies. A nationwide retrospective cohort study was conducted. The Dutch National Trauma Database was used to identify all patients over 17 years old who were admitted to a hospital with moderate and severe TBI (AIS ≥ 3) in the Netherlands from January 2015 until December 2017. Subgroup analyses were done for the elderly and polytrauma patients. 12,295 patients were included in this study. The incidence of moderate and severe TBI was 30/100.000 person-years, 13% of whom died. Median age was 65 years and falls were the most common trauma mechanism, followed by RTAs. Amongst elderly, RTAs consisted mostly of bicycle accidents. Mortality rates were higher for elderly (18%) and polytrauma patients (24%). In this national database more elderly patients who most often sustained the injury due to a fall or an RTA were seen. Bicycle accidents were very frequent, suggesting prevention could be an important aspect in order to decrease morbidity and mortality., (© 2021. The Author(s).)
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- 2021
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47. Distinctive pattern of temporal atrophy in patients with frontotemporal dementia and the I383V variant in TARDBP .
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Mol MO, Nijmeijer SWR, van Rooij JGJ, van Spaendonk RML, Pijnenburg YAL, van der Lee SJ, van Minkelen R, Donker Kaat L, Rozemuller AJM, Janse van Mantgem MR, van Rheenen W, van Es MA, Veldink JH, Hennekam FAM, Vernooij M, van Swieten JC, Cohn-Hokke PE, Seelaar H, and Dopper EGP
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- Adult, Aged, Atrophy genetics, Atrophy pathology, Female, Frontotemporal Dementia genetics, Humans, Male, Middle Aged, DNA-Binding Proteins genetics, Frontotemporal Dementia pathology, Temporal Lobe pathology
- Abstract
Competing Interests: Competing interests: Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases: Project ID No. 739510. JHV reports to have sponsored research agreements with Biogen.
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- 2021
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48. Screening for cognition in amyotrophic lateral sclerosis: test characteristics of a new screen.
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Beeldman E, Govaarts R, de Visser M, van Es MA, Pijnenburg YAL, Schmand BA, and Raaphorst J
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- Cognition, Humans, Neuropsychological Tests, Quality of Life, Amyotrophic Lateral Sclerosis complications, Amyotrophic Lateral Sclerosis diagnosis, Cognition Disorders diagnosis, Cognition Disorders etiology, Frontotemporal Dementia complications, Frontotemporal Dementia diagnosis
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Cognitive and behavioural impairment in amyotrophic lateral sclerosis (ALS) negatively influences the quality of life and survival, and, therefore, screening for these impairments is recommended. We developed a cognitive screening tool, the amyotrophic lateral sclerosis-frontotemporal dementia-cognitive screen (ALS-FTD-Cog) and aimed to validate it in patients with ALS. During the current study, the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was published and we, therefore, decided to compare these two cognitive screening methods. The ALS-FTD-Cog was administered to 72 patients with ALS, 21 patients with behavioural variant FTD (bvFTD) and 34 healthy controls. Twenty-nine patients with ALS underwent the ECAS. ROC curve analyses were performed and sensitivity and specificity of the ALS-FTD-Cog and ECAS were calculated, with a neuropsychological examination (NPE) as the gold standard. Cognitive impairment was present in 28% of patients with ALS. ROC curve analyses of the ALS-FTD-Cog and ECAS showed an area under the curve (AUC) of 0.72 (95% CI 0.58-0.86) and 0.95 (95% CI 0.86-1.03), respectively. Compared to a full NPE, sensitivity and specificity of the ALS-FTD-Cog were 65.0% and 63.5% and of the ECAS 83.3% and 91.3%, respectively. The sensitivity and specificity of the ALS-FTD-Cog in patients with bvFTD were 94.4% and 100%, respectively. Test characteristics of the ALS-FTD-Cog were moderate, suggesting restricted practical value, as compared to a comprehensive NPE. The ECAS had an excellent AUC and high sensitivity and specificity, indicating that it is a valid screening instrument for cognitive impairment in ALS.
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- 2021
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49. Facial Onset Sensory and Motor Neuronopathy: New Cases, Cognitive Changes, and Pathophysiology.
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de Boer EMJ, Barritt AW, Elamin M, Anderson SJ, Broad R, Nisbet A, Goedee HS, Vázquez Costa JF, Prudlo J, Vedeler CA, Fernandez JP, Panades MP, Albertí Aguilo MA, Bella ED, Lauria G, Pinto WBVR, de Souza PVS, Oliveira ASB, Toro C, van Iersel J, Parson M, Harschnitz O, van den Berg LH, Veldink JH, Al-Chalabi A, Leigh PN, and van Es MA
- 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., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2021
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50. Incidence, Prevalence, and Geographical Clustering of Motor Neuron Disease in the Netherlands.
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de Jongh AD, van Eijk RPA, Peters SM, van Es MA, Horemans AMC, van der Kooi AJ, Voermans NC, Vermeulen RCH, Veldink JH, and van den Berg LH
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Objective: To 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., Methods: In 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., Results: We 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., Conclusions: We 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., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2021
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