477 results on '"Van Es, Michael A."'
Search Results
152. Rhabdomyolysis after COVID-19 Comirnaty Vaccination: A Case Report.
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Ruijters, Veerle J., van der Meulen, Marjon F.G., van Es, Michael A., Smit, Tessa, and Hoogendijk, Jessica E.
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COVID-19 vaccines , *RHABDOMYOLYSIS , *CREATINE kinase , *COVID-19 , *MUSCLE weakness , *KIDNEY failure - 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. [ABSTRACT FROM AUTHOR]
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- 2022
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153. Cognitive and behavioural changes in PLS and PMA:challenging the concept of restricted phenotypes.
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Turner, Martin R., de Vries, Bálint S, Rustemeijer, Laura M M, Bakker, Leonhard A, Schröder, Carin D, Veldink, Jan H, van den Berg, Leonard H, Nijboer, Tanja C W, and van Es, Michael A
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SPINAL muscular atrophy ,MONTREAL Cognitive Assessment ,FRONTOTEMPORAL dementia ,MOTOR neuron diseases ,AMYOTROPHIC lateral sclerosis - Abstract
Objectives: Cognitive and behavioural changes within the spectrum of frontotemporal dementia (FTD) are observed frequently in patients with amyotrophic lateral sclerosis (ALS). Whether these changes also occur in other forms of motor neuron disease (MND) is not well studied. We therefore systemically screened a large cohort of patients with primary lateral sclerosis (PLS) and progressive muscular atrophy (PMA) for cognitive and behavioural changes, and subsequently compared our findings with a cohort of patients with ALS.Methods: Using a set of screening instruments (Edinburgh Cognitive and Behavioural ALS Screen, ALS and Frontotemporal Dementia Questionnaire, Frontal Assessment Battery, and Hospital Anxiety and Depression Scale), the presence of cognitive and behavioural changes as well as anxiety and depression in 277 patients with ALS, 75 patients with PLS and 143 patients with PMA was evaluated retrospectively.Results: We found a high frequency of cognitive and behavioural abnormalities with similar profiles in all three groups. Subjects with behavioural variant FTD were identified in all groups.Conclusions: The percentage of patients with PLS and PMA with cognitive dysfunction was similar to patients with ALS, emphasising the importance for cognitive screening as part of routine clinical care in all three patient groups. With a similar cognitive profile, in line with genetic and clinical overlap between the MNDs, the view of PLS as an MND exclusively affecting upper motor neurons and PMA exclusively affecting lower motor neurons cannot be held. Therefore, our findings are in contrast to the recently revised El Escorial criteria of 2015, where PLS and PMA are described as restricted phenotypes. Our study favours a view of PLS and PMA as multidomain diseases similar to ALS. [ABSTRACT FROM AUTHOR]- Published
- 2019
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154. Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis.
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van Es, Michael A., van Vught, Paul W. J., Blauw, Hylke M., Franke, Lude, Saris, Christiaan G. J., Van Den Bosch, Ludo, de Jong, Sonja W., de Jong, Vianney, Baas, Frank, van't Slot, Ruben, Lemmens, Robin, Schelhaas, Helenius J., Birve, Anna, Sleegers, Kristel, Van Broeckhoven, Christine, Schymick, Jennifer C., Traynor, Bryan J., Wokke, John H. J., Wijmenga, Cisca, and Robberecht, Wim
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AMYOTROPHIC lateral sclerosis , *GENES , *EUROPEANS , *MOTOR neuron diseases , *GENETICS , *MEDICAL genetics - Abstract
We identified a SNP in the DPP6 gene that is consistently strongly associated with susceptibility to amyotrophic lateral sclerosis (ALS) in different populations of European ancestry, with an overall P value of 5.04 × 10−8 in 1,767 cases and 1,916 healthy controls and with an odds ratio of 1.30 (95% confidence interval (CI) of 1.18–1.43). Our finding is the first report of a genome-wide significant association with sporadic ALS and may be a target for future functional studies. [ABSTRACT FROM AUTHOR]
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- 2008
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155. Refining eligibility criteria for amyotrophic lateral sclerosis clinical trials.
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van Eijk, Ruben P. A., Westeneng, Henk-Jan, Nikolakopoulos, Stavros, Verhagen, Iris E, van Es, Michael A, Eijkemans, Marinus J C, and van den Berg, Leonard H
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- 2019
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156. 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, Iris F., Van Eijk, Ruben P.A., Van Boxmeer, Loes, Westeneng, Henk-Jan, Van Es, Michael A., Van Rheenen, Wouter, Van Den Berg, Leonard H., Eijkemans, Marinus J.C., and Veldink, Jan H.
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RISK assessment , *RANDOM effects model , *RELATIVES - Abstract
We aimed to estimate the age-related risk of ALS in first-degree relatives of patients with ALS carrying the C9orf72 repeat expansion. 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. 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. 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. [ABSTRACT FROM AUTHOR]
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- 2024
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157. Familial motor neuron disease: co-occurrence of PLS and ALS (-FTD).
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de Boer, Eva M. J., Demaegd, Koen C., de Bie, Charlotte I., Veldink, Jan H., van den Berg, Leonard H., and van Es, Michael A.
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MOTOR neuron diseases , *SPINAL muscular atrophy , *AMYOTROPHIC lateral sclerosis , *LITERATURE reviews , *PATIENTS' families - Abstract
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. 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. 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. 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. [ABSTRACT FROM AUTHOR]
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- 2024
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158. Discussing personalized prognosis in amyotrophic lateral sclerosis: development of a communication guide.
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van Eenennaam, Remko M., Kruithof, Willeke J., van Es, Michael A., Kruitwagen-van Reenen, Esther T., Westeneng, Henk-Jan, Visser-Meily, Johanna M. A., van den Berg, Leonard H., and Beelen, Anita
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AMYOTROPHIC lateral sclerosis , *PATIENTS' families , *PATIENT preferences , *SURVIVAL analysis (Biometry) , *COGNITION disorders , *FRONTOTEMPORAL lobar degeneration , *VASCULAR dementia - Abstract
Background: Personalized ENCALS survival prediction model reliably estimates the personalized prognosis of patients with amyotrophic lateral sclerosis. Concerns were raised on discussing personalized prognosis without causing anxiety and destroying hope. Tailoring communication to patient readiness and patient needs mediates the impact of prognostic disclosure. We developed a communication guide to support physicians in discussing personalized prognosis tailored to individual needs and preferences of people with ALS and their families.Methods: A multidisciplinary working group of neurologists, rehabilitation physicians, and healthcare researchers A) identified relevant topics for guidance, B) conducted a systematic review on needs of patients regarding prognostic discussion in life-limiting disease, C) drafted recommendations based on evidence and expert opinion, and refined and finalized these recommendations in consensus rounds, based on feedback of an expert advisory panel (patients, family member, ethicist, and spiritual counsellor).Results: A) Topics identified for guidance were 1) filling in the ENCALS survival model, and interpreting outcomes and uncertainty, and 2) tailoring discussion to individual needs and preferences of patients (information needs, role and needs of family, severe cognitive impairment or frontotemporal dementia, and non-western patients). B) 17 studies were included in the systematic review. C) Consensus procedures on drafted recommendations focused on selection of outcomes, uncertainty about estimated survival, culturally sensitive communication, and lack of decisional capacity. Recommendations for discussing the prognosis include the following: discuss prognosis based on the prognostic groups and their median survival, or, if more precise information is desired, on the interquartile range of the survival probability. Investigate needs and preferences of the patients and their families for prognostic disclosure, regardless of cultural background. If the patient does not want to know their prognosis, with patient permission discuss the prognosis with their family. If the patient is judged to lack decisional capacity, ask the family if they want to discuss the prognosis. Tailor prognostic disclosure step by step, discuss it in terms of time range, and emphasize uncertainty of individual survival time.Conclusion: This communication guide supports physicians in tailoring discussion of personalized prognosis to the individual needs and preferences of people with ALS and their families. [ABSTRACT FROM AUTHOR]- Published
- 2020
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159. Genetic characterization of primary lateral sclerosis.
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de Boer, Eva M. J., de Vries, Balint S., Pennings, Maartje, Kamsteeg, Erik-Jan, Veldink, Jan H., van den Berg, Leonard H., and van Es, Michael A.
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AMYOTROPHIC lateral sclerosis , *FAMILIAL spastic paraplegia , *MOTOR neuron diseases , *MOVEMENT disorders , *MOTOR neurons - 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. [ABSTRACT FROM AUTHOR]
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- 2023
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160. Outcomes after robotic thymectomy in nonthymomatous versus thymomatous patients with acetylcholine-receptor-antibody-associated myasthenia gravis.
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Marcuse, Florit, Hoeijmakers, Janneke G.J., Hochstenbag, Monique, Hamid, Myrurgia Abdul, Keijzers, Marlies, Mané-Damas, Marina, Martinez-Martinez, Pilar, Verschuuren, Jan, Kuks, Jan, Beekman, Roy, van der Kooi, Anneke J., van Doorn, Pieter, van Es, Michael, Maessen, Jos J.G., and De Baets, Marc H.V.
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MYASTHENIA gravis , *THYMECTOMY , *ROBOTICS , *PATIENT safety - Abstract
• Robotic thymectomy is safe and feasible in patients with myasthenia gravis. • The majority of the patients (82.4%) improved in MG manifestations after robotic thymectomy. • MG remission was observed in 47.8% of the patients after thymectomy (mean: 26.2 months). • Thymomatous patients had more frequently complications compared to nonthymomatous patients. The aim of this study was to investigate the surgical and long-term neurological outcomes of patients with acetylcholine-receptor-antibody-associated myasthenia gravis (AChR-MG) who underwent robotic thymectomy (RATS). We retrospectively analyzed the clinical-pathological data of all patients with AChR-MG who underwent RATS using the DaVinci® Robotic System at the MUMC+ between April 2004 and December 2018. Follow-up data were collected from 60 referring Dutch hospitals. In total, 230 myasthenic patients including 76 patients with a thymoma (33.0%) were enrolled in this study. Mean follow-up time, procedure time and hospitalization were, respectively 65.7 ± 43.1 months, 111±52.5 min and 3.3 ± 2.2 days. Thymomatous patients had significantly more frequently and more severe complications than nonthymomatous patients (18.4% vs. 3.9%, p <0.001). Follow up data was available in 71.7% of the included patients. The Myasthenia Gravis Foundation of America postintervention score showed any kind of improvement of MG-symptoms after RATS in 82.4% of the patients. Complete stable remission (CSR) or pharmacological remission (PR) of MG was observed in 8.4% and 39.4% of the patients, respectively. Mean time till CSR/PR remission after thymectomy was 26.2 ± 29.2 months. No statistical difference was found in remission or improvement in MGFA scale between thymomatous and nonthymomatous patients. RATS is safe and feasible in patients with MG. The majority of the patients (82.4%) improved after thymectomy. CSR and PR were observed in 8.4% and 39.4% of the patients, respectively, with a mean of 26.2 months after thymectomy. Thymomatous patients had more frequently and more severe complications compared to nonthymomatous patients. [ABSTRACT FROM AUTHOR]
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- 2023
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161. Longitudinal Effects of Asymptomatic C9orf72 Carriership on Brain Morphology.
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van Veenhuijzen, Kevin, Westeneng, Henk‐Jan, Tan, Harold H. G., Nitert, Abram D., van der Burgh, Hannelore K., Gosselt, Isabel, van Es, Michael A., Nijboer, Tanja C. W., Veldink, Jan H., and van den Berg, Leonard H.
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EFFERENT pathways , *PARIETAL lobe , *MOTOR cortex , *MORPHOLOGY , *AMYOTROPHIC lateral sclerosis - 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 [ABSTRACT FROM AUTHOR]
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- 2023
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162. Nepal's Constitutional Standoff Threatens Its Transition.
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Vurens van Es, Michael
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PUBLIC demonstrations ,CONSTITUTIONS ,POLITICAL systems ,NEPALI politics & government ,POLITICAL parties - Abstract
The article discusses the unstable situation in Nepal following the failure of a 2nd Constituent Assembly to announce a constitution before January 22, 2015. Topics cited include the impact of the ongoing protests on the country's commerce, the importance of ramifications for the constitution's credibility and the apparent minimal feats achieved in February 2014 by the Nepali Congress and the social democratic Communist Party of Nepal (Unified Marxist Leninist), known as CPN-UML.
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- 2015
163. Assessment of the factorial validity and reliability of the ALSFRS-R: a revision of its measurement model.
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Bakker, Leonhard, Schröder, Carin, Van Es, Michael, Westers, Paul, Visser-Meily, Johanna, and Van Den Berg, Leonard
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AMYOTROPHIC lateral sclerosis , *CONFIRMATORY factor analysis , *EPIDEMIOLOGICAL research , *FACTOR structure , *MODELS (Patents) - Abstract
The amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) is a widely used primary outcome measure in amyotrophic lateral sclerosis (ALS) clinical practice and clinical trials. ALSFRS-R items cannot, however, validly be summed to obtain a total score, but constitute domain scores reflecting a profile of disease severity. Currently, there are different measurement models for estimating domain scores. The objective of the present study is, therefore, to derive the measurement model that best fits the data for a valid and uniform estimation of ALSFRS-R domain scores. Data from 1556 patients with ALS were obtained from a population-based register in The Netherlands. A random split of the sample provided a calibration and validation set. Measurement models of the ALSFRS-R were investigated using both exploratory factor analyses and confirmatory factor analyses. The measurement model with a four-factor structure (i.e., bulbar, fine motor, gross motor, and respiratory function), with correlated factors and cross-loading items on dressing and hygiene and turning in bed and adjusting bed clothes on both motor function scales, provided the best fit to the data in both sets. Correlation between factors ranged from weak to modest, confirming that the ALSFRS-R constitutes a profile of four clinically relevant domain scores rather than a total score that expresses disease severity. The internal consistency of the four domain scores was satisfactory. Our revision of the measurement model may allow for a more adequate estimation of disease severity and disease progression in epidemiological studies and clinical trials. [ABSTRACT FROM AUTHOR]
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- 2017
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164. 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, Sean W., Roes, Kit C. B., Van Damme, Philip, Hardiman, Orla, Ingre, Caroline, Povedano, Monica, Wray, Naomi R., Gijzen, Marleen, de Pagter, Mirjam S., Demaegd, Koen C., Janse, Annemarie F. C., Vink, Roel G., Sleutjes, Boudewijn T. H. M., Chiò, Adriano, Corcia, Philippe, Reviers, Evy, Al-Chalabi, Ammar, Kiernan, Matthew C., van den Berg, Leonard H., and van Es, Michael A.
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AMYOTROPHIC lateral sclerosis , *LITHIUM carbonate , *SINGLE nucleotide polymorphisms , *RESPIRATORY insufficiency , *GENETIC polymorphisms - 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. [ABSTRACT FROM AUTHOR]- Published
- 2022
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165. MRI Clustering Reveals Three ALS Subtypes With Unique Neurodegeneration Patterns.
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Tan, Harold H. G., Westeneng, Henk‐Jan, Nitert, Abram D., van Veenhuijzen, Kevin, Meier, Jil M., van der Burgh, Hannelore K., van Zandvoort, Martine J. E., van Es, Michael A., Veldink, Jan H., and van den Berg, Leonard H.
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DIFFUSION tensor imaging , *FRONTAL lobe , *AMYOTROPHIC lateral sclerosis , *CINGULATE cortex , *MAGNETIC resonance imaging , *FRONTOTEMPORAL lobar degeneration - 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 [ABSTRACT FROM AUTHOR]
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- 2022
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166. 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, Denise, van Rein, Eveline, Niemeijer, Menco, van Heijl, Mark, van Es, Michael A., Nijboer, Tanja, Leenen, Luke P. H., Houwert, R. Marijn, and van Wessem, Karlijn J. P.
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BRAIN injuries , *OLDER patients , *CAUSES of death , *WOUNDS & injuries , *TRAFFIC accidents , *CYCLING accidents - Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability. Epidemiology seems to be changing. TBIs are increasingly caused by falls amongst elderly, whilst we see less polytrauma due to road traffic accidents (RTA). Data on epidemiology is essential to target prevention strategies. A nationwide retrospective cohort study was conducted. The Dutch National Trauma Database was used to identify all patients over 17 years old who were admitted to a hospital with moderate and severe TBI (AIS ≥ 3) in the Netherlands from January 2015 until December 2017. Subgroup analyses were done for the elderly and polytrauma patients. 12,295 patients were included in this study. The incidence of moderate and severe TBI was 30/100.000 person-years, 13% of whom died. Median age was 65 years and falls were the most common trauma mechanism, followed by RTAs. Amongst elderly, RTAs consisted mostly of bicycle accidents. Mortality rates were higher for elderly (18%) and polytrauma patients (24%). In this national database more elderly patients who most often sustained the injury due to a fall or an RTA were seen. Bicycle accidents were very frequent, suggesting prevention could be an important aspect in order to decrease morbidity and mortality. [ABSTRACT FROM AUTHOR]
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- 2021
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167. Screening for cognition in amyotrophic lateral sclerosis: test characteristics of a new screen.
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Beeldman, Emma, Govaarts, Rosanne, de Visser, Marianne, van Es, Michael A., Pijnenburg, Yolande A. L., Schmand, Ben A., and Raaphorst, Joost
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AMYOTROPHIC lateral sclerosis , *COGNITION , *SENSITIVITY & specificity (Statistics) , *COGNITION disorders , *RECEIVER operating characteristic curves - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2021
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168. Senataxin mutations elicit motor neuron degeneration phenotypes and yield TDP-43 mislocalization in ALS4 mice and human patients.
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Bennett, Craig L., Dastidar, Somasish G., Ling, Shuo-Chien, Malik, Bilal, Ashe, Travis, Wadhwa, Mandheer, Miller, Derek B., Lee, Changwoo, Mitchell, Matthew B., Van Es, Michael A., Grunseich, Christopher, Chen, Yingzhang, Sopher, Bryce L., Greensmith, Linda, Cleveland, Don W., and La Spada, Albert R.
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MOTOR neuron diseases , *AMYOTROPHIC lateral sclerosis - Abstract
Amyotrophic lateral sclerosis type 4 (ALS4) is a rare, early-onset, autosomal dominant form of ALS, characterized by slow disease progression and sparing of respiratory musculature. Dominant, gain-of-function mutations in the senataxin gene (SETX) cause ALS4, but the mechanistic basis for motor neuron toxicity is unknown. SETX is a RNA-binding protein with a highly conserved helicase domain, but does not possess a low-complexity domain, making it unique among ALS-linked disease proteins. We derived ALS4 mouse models by expressing two different senataxin gene mutations (R2136H and L389S) via transgenesis and knock-in gene targeting. Both approaches yielded SETX mutant mice that develop neuromuscular phenotypes and motor neuron degeneration. Neuropathological characterization of SETX mice revealed nuclear clearing of TDP-43, accompanied by TDP-43 cytosolic mislocalization, consistent with the hallmark pathology observed in human ALS patients. Postmortem material from ALS4 patients exhibited TDP-43 mislocalization in spinal cord motor neurons, and motor neurons from SETX ALS4 mice displayed enhanced stress granule formation. Immunostaining analysis for nucleocytoplasmic transport proteins Ran and RanGAP1 uncovered nuclear membrane abnormalities in the motor neurons of SETX ALS4 mice, and nuclear import was delayed in SETX ALS4 cortical neurons, indicative of impaired nucleocytoplasmic trafficking. SETX ALS4 mice thus recapitulated ALS disease phenotypes in association with TDP-43 mislocalization and provided insight into the basis for TDP-43 histopathology, linking SETX dysfunction to common pathways of ALS motor neuron degeneration. [ABSTRACT FROM AUTHOR]
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- 2018
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169. The effect of SMN gene dosage on ALS risk and disease severity
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Vincenzo Silani, Mamede de Carvalho, Nicola Ticozzi, Joke J.F.A. van Vugt, Kristel R. van Eijk, Patrick Vourc'h, Markus Weber, Wouter van Rheenen, Kevin P. Kenna, Christopher Shaw, Wim Robberecht, Philippe Couratier, Mònica Povedano, Jonathan D. Glass, Pamela J. Shaw, Ramona A. J. Zwamborn, Ammar Al-Chalabi, John Landers, Michael A. Eberle, Michael A. van Es, Xiao Chen, Leonard H. van den Berg, Brendan J. Kenna, Philippe Corcia, Karen E. Morrison, Marc Gotkine, Russell McLaughin, Peter M. Andersen, Matthieu Moisse, Philip Van Damme, Rick A.A. van der Spek, Jesus S. Mora Pardina, Orla Hardiman, Vivian E. Drory, Jan H. Veldink, Nazli Basak, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Moisse, Matthieu, Zwamborn, Ramona A. J., van Vugt, Joke, van Der Spek, Rick, van Rheenen, Wouter, Kenna, Brendan, Van Eijk, Kristel, Kenna, Kevin, Corcia, Philippe, Couratier, Philippe, Vourc'h, Patrick, Hardiman, Orla, McLaughin, Russell, Gotkine, Marc, Drory, Vivian, Ticozzi, Nicola, Silani, Vincenzo, de Carvalho, Mamede, Mora Pardina, Jesus S., Povedano, Monica, Andersen, Peter M., Weber, Markus, Chen, Xiao, Eberle, Michael A., Al-Chalabi, Ammar, Shaw, Chris, Shaw, Pamela J., Morrison, Karen E., Landers, John E., Glass, Jonathan D., Robberecht, Wim, van Es, Michael, van den Berg, Leonard, Veldink, Jan, Van Damme, Philip, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Université de Leuven, Katholiek Universiteit Leuven, Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Service de Neurologie [CHU Limoges], CHU Limoges, UMR U 1253, Department of Neurology, The Adelaide and Meath Hospital, Trinity College Dublin, Trinity College, Trinity College Dublin, Tel Aviv Sourasky Medical Center [Te Aviv], Department of Neurology, IRCCS San Raffaele, Milano, Université de Lisbonne, Sant Rafael Hospital, Umeå University Hospital, Umea University Hospital, Illumina Incorporated [San Diego, CA, USA], Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield [Sheffield], Queen's University [Belfast] (QUB), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Emory University School of Medicine, Emory University [Atlanta, GA], University Hospitals Leuven [Leuven], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), Grelier, Elisabeth, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-CHU Limoges-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST)
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0301 basic medicine ,Male ,Neurologi ,Survival of Motor Neuron 2 Protein/genetics ,Clinical Neurology ,Gene Dosage ,SMN1 ,Bioinformatics ,Logistic regression ,Severity of Illness Index ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,medicine ,Survival of Motor Neuron 1 Protein/genetics ,Humans ,Amyotrophic lateral sclerosis ,Gene ,Research Articles ,Whole genome sequencing ,Science & Technology ,Whole Genome Sequencing ,business.industry ,Project MinE ,Amyotrophic Lateral Sclerosis ,Neurosciences ,Case-control study ,Reproducibility of Results ,Survival of motor neuron ,Amyotrophic Lateral Sclerosis/genetics ,medicine.disease ,Survival of Motor Neuron 1 Protein ,3. Good health ,nervous system diseases ,Survival of Motor Neuron 2 Protein ,030104 developmental biology ,Neurology ,[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie ,Case-Control Studies ,Female ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Medicine ,Clinical neurology ,Neurosciences & Neurology ,Neurology (clinical) ,business ,Life Sciences & Biomedicine ,030217 neurology & neurosurgery ,Research Article - Abstract
Objective: the role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency. Methods: in this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data. Results: the copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63). Interpretation: in our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies., European Union (EU); Horizon 2020; European Research Council (ERC); Research and Innovation Programme; EScORIAL; IWT; FWO-Vlaanderen; United Kingdom Medical Research Council; Neurodegenerative Disease Research (JPND); Netherlands; ZONMW; BRAIN-MEND; NIH/NINDS; Italian Ministry of Health; Fondazione Regionale per la Ricerca Biomedica Regione Lombardia; Science Foundation Ireland; ALS Liga Belgie; National Lottery of Belgium; KU Leuven Opening the Future Fund; E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders; ALS Foundation Netherlands; PPP Allowance; Motor Neurone Disease Association; National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre; Fondazione Italiana di Ricerca per la SLA - AriSLA; Exomefals; Novals; ALS Association; E-RARE JTC Project Repetomics
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- 2021
170. Mapping of Gene Expression Reveals CYP27A1 as a Susceptibility Gene for Sporadic ALS.
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Diekstra, Frank P., Saris, Christiaan G. J., Rheenen, Wouter van, Franke, Lude, Jansen, Ritsert C., van Es, Michael A., van Vught, Paul W. J., Blauw, Hylke M., Groen, Ewout J. N., Horvath, Steve, Estrada, Karol, Rivadeneira, Fernando, Hofman, Albert, Uitterlinden, Andre G., Robberecht, Wim, Andersen, Peter M., Melki, Judith, Meininger, Vincent, Hardiman, Orla, and Landers, John E.
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AMYOTROPHIC lateral sclerosis , *NEURONS , *GENE expression , *GENETIC regulation , *SPINAL cord , *MOTOR neurons - Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls) were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls). These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls). Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27×10-51) withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible susceptibility gene for ALS. [ABSTRACT FROM AUTHOR]
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- 2012
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171. STrengthening the Reporting Of Pharmacogenetic Studies: Development of the STROPS guideline
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Marty Chaplin, Jamie J. Kirkham, Kerry Dwan, Derek J. Sloan, Geraint Davies, Andrea L. Jorgensen, Irma Aguilar-Delfín, José A G Agúndez, Sophie M Argon, M J Arranz, Derrick A Bennett, Stefan Böhringer, Lawrence Brody, Ingolf Cascorbi, Erika Cecchin, Mandy Crommentuijn-van Rhenen, Ann K Daly, Nur Aizati Athirah Daud, Jorge Duconge, Chiara Fabbri, Alison Fitches, Andrea Gaedigk, Donato Gemmati, Claudia Maria Dan Hawcutt, Rachel Huddart, Evelyne Jacqz-Aigrain, Slobodan M Janković, Theodora Katsila, Gideon Koren, Beata S Lipska-Ziętkiewicz, Thomas Liehr, A H Maitland-van der Zee, Lisanne E N Manson, Martin H Maurer, Juan Eduardo Megías-Vericat, Taichi Ochi, Daniel J O'Connor, Laura B Ramsey, Gad Rennert, Francesco Rucci, Gaetano Santulli, Aris Saoulidis, Rashmi R Shah, Alessandro Serretti, Andrew Somogyi, Gere Sunder-Plassmann, Virginia Boso-Ribelles, Caroline F Thorn, Evangelia Eirini Tsermpini, Satyanarayana Chakradhara Rao Uppugunduri, Michael A van Es, Magdalena Zarowiecki, University of St Andrews. School of Medicine, University of St Andrews. Infection and Global Health Division, Chaplin, Marty, Kirkham, Jamie J., Dwan, Kerry, Sloan, Derek J., Davies, Geraint, Jorgensen, Andrea L., Aguilar-Delfín, Irma, G Agúndez, José A, M Argon, Sophie, J Arranz, M, A Bennett, Derrick, Böhringer, Stefan, Brody, Lawrence, Cascorbi, Ingolf, Cecchin, Erika, Crommentuijn-van Rhenen, Mandy, K Daly, Ann, Aizati Athirah Daud, Nur, Duconge, Jorge, Fabbri, Chiara, Fitches, Alison, Gaedigk, Andrea, Gemmati, Donato, Maria Dan Hawcutt, Claudia, Huddart, Rachel, Jacqz-Aigrain, Evelyne, M Janković, Slobodan, Katsila, Theodora, Koren, Gideon, S Lipska-Ziętkiewicz, Beata, Liehr, Thoma, H Maitland-van der Zee, A, N Manson, Lisanne E, H Maurer, Martin, Eduardo Megías-Vericat, Juan, Ochi, Taichi, J O'Connor, Daniel, B Ramsey, Laura, Rennert, Gad, Rucci, Francesco, Santulli, Gaetano, Saoulidis, Ari, R Shah, Rashmi, Serretti, Alessandro, Somogyi, Andrew, Sunder-Plassmann, Gere, Boso-Ribelles, Virginia, F Thorn, Caroline, Eirini Tsermpini, Evangelia, Chakradhara Rao Uppugunduri, Satyanarayana, A van Es, Michael, and Zarowiecki, Magdalena
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Male ,Delphi Technique ,Delphi method ,Surveys ,030204 cardiovascular system & hematology ,Guidelines and Guidance ,Mathematical and Statistical Techniques ,0302 clinical medicine ,Surveys and Questionnaires ,Medicine and Health Sciences ,030212 general & internal medicine ,Statistics ,Politics ,Stakeholder ,Genomics ,General Medicine ,Research Assessment ,Metaanalysis ,Middle Aged ,Checklist ,Systematic review ,Research Design ,Physical Sciences ,Research Reporting Guidelines ,Medicine ,Engineering and Technology ,Female ,Goals ,Biotechnology ,Adult ,RM ,medicine.medical_specialty ,Drug Research and Development ,Consensus ,Systematic Reviews ,MEDLINE ,Bioengineering ,Research and Analysis Methods ,03 medical and health sciences ,Genomic Medicine ,Stakeholder Participation ,Genetics ,medicine ,Humans ,Statistical Methods ,Genetic Association Studies ,Pharmacology ,Publishing ,Survey Research ,business.industry ,Biology and Life Sciences ,DAS ,Guideline ,United Kingdom ,RM Therapeutics. Pharmacology ,Pharmacogenomic Testing ,Pharmacogenetics ,Sample size determination ,Family medicine ,Pharmacogenomics ,business ,Mathematics - Abstract
Background Large sample sizes are often required to detect statistically significant associations between pharmacogenetic markers and treatment response. Meta-analysis may be performed to synthesize data from several studies, increasing sample size and, consequently, power to detect significant genetic effects. However, performing robust synthesis of data from pharmacogenetic studies is often challenging because of poor reporting of key data in study reports. There is currently no guideline for the reporting of pharmacogenetic studies that has been developed using a widely accepted robust methodology. The objective of this project was to develop the STrengthening the Reporting Of Pharmacogenetic Studies (STROPS) guideline. Methods and findings We established a preliminary checklist of reporting items to be considered for inclusion in the guideline. We invited representatives of key stakeholder groups to participate in a 2-round Delphi survey. A total of 52 individuals participated in both rounds of the survey, scoring items with regards to their importance for inclusion in the STROPS guideline. We then held a consensus meeting, at which 8 individuals considered the results of the Delphi survey and voted on whether each item ought to be included in the final guideline. The STROPS guideline consists of 54 items and is accompanied by an explanation and elaboration document. The guideline contains items that are particularly important in the field of pharmacogenetics, such as the drug regimen of interest and whether adherence to treatment was accounted for in the conducted analyses. The guideline also requires that outcomes be clearly defined and justified, because in pharmacogenetic studies, there may be a greater number of possible outcomes than in other types of study (for example, disease–gene association studies). A limitation of this project is that our consensus meeting involved a small number of individuals, the majority of whom are based in the United Kingdom. Conclusions Our aim is for the STROPS guideline to improve the transparency of reporting of pharmacogenetic studies and also to facilitate the conduct of high-quality systematic reviews and meta-analyses. We encourage authors to adhere to the STROPS guideline when publishing pharmacogenetic studies., Marty Chaplin and co-authors recount the development of a guideline for reporting pharmacogenetic studies.
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- 2020
172. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
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Aude Nicolas, Kevin P. Kenna, Alan E. Renton, Nicola Ticozzi, Faraz Faghri, Ruth Chia, Janice A. Dominov, Brendan J. Kenna, Mike A. Nalls, Pamela Keagle, Alberto M. Rivera, Wouter van Rheenen, Natalie A. Murphy, Joke J.F.A. van Vugt, Joshua T. Geiger, Rick A. Van der Spek, Hannah A. Pliner, null Shankaracharya, Bradley N. Smith, Giuseppe Marangi, Simon D. Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, Gabriele Mora, Andrea Calvo, Letizia Mazzini, Nilo Riva, Jessica Mandrioli, Claudia Caponnetto, Stefania Battistini, Paolo Volanti, Vincenzo La Bella, Francesca L. Conforti, Giuseppe Borghero, Sonia Messina, Isabella L. Simone, Francesca Trojsi, Fabrizio Salvi, Francesco O. Logullo, Sandra D’Alfonso, Lucia Corrado, Margherita Capasso, Luigi Ferrucci, Cristiane de Araujo Martins Moreno, Sitharthan Kamalakaran, David B. Goldstein, Aaron D. Gitler, Tim Harris, Richard M. Myers, Hemali Phatnani, Rajeeva Lochan Musunuri, Uday Shankar Evani, Avinash Abhyankar, Michael C. Zody, Julia Kaye, Steven Finkbeiner, Stacia K. Wyman, Alex LeNail, Leandro Lima, Ernest Fraenkel, Clive N. Svendsen, Leslie M. Thompson, Jennifer E. Van Eyk, James D. Berry, Timothy M. Miller, Stephen J. Kolb, Merit Cudkowicz, Emily Baxi, Michael Benatar, J. Paul Taylor, Evadnie Rampersaud, Gang Wu, Joanne Wuu, Giuseppe Lauria, Federico Verde, Isabella Fogh, Cinzia Tiloca, Giacomo P. Comi, Gianni Sorarù, Cristina Cereda, Philippe Corcia, Hannu Laaksovirta, Liisa Myllykangas, Lilja Jansson, Miko Valori, John Ealing, Hisham Hamdalla, Sara Rollinson, Stuart Pickering-Brown, Richard W. Orrell, Katie C. Sidle, Andrea Malaspina, John Hardy, Andrew B. Singleton, Janel O. Johnson, Sampath Arepalli, Peter C. Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, Safa Al-Sarraj, Andrew King, Claire Troakes, Caroline Vance, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, José Luis Muñoz-Blanco, Dena G. Hernandez, Jinhui Ding, J. Raphael Gibbs, Sonja W. Scholz, Mary Kay Floeter, Roy H. Campbell, Francesco Landi, Robert Bowser, Stefan M. Pulst, John M. Ravits, Daniel J.L. MacGowan, Janine Kirby, Erik P. Pioro, Roger Pamphlett, James Broach, Glenn Gerhard, Travis L. Dunckley, Christopher B. Brady, Neil W. Kowall, Juan C. Troncoso, Isabelle Le Ber, Kevin Mouzat, Serge Lumbroso, Terry D. Heiman-Patterson, Freya Kamel, Ludo Van Den Bosch, Robert H. Baloh, Tim M. Strom, Thomas Meitinger, Aleksey Shatunov, Kristel R. Van Eijk, Mamede de Carvalho, Maarten Kooyman, Bas Middelkoop, Matthieu Moisse, Russell L. McLaughlin, Michael A. Van Es, Markus Weber, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Karen E. Morrison, A. Nazli Basak, Jesús S. Mora, Vivian E. Drory, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Orla Hardiman, Kelly L. Williams, Jennifer A. Fifita, Garth A. Nicholson, Ian P. Blair, Guy A. Rouleau, Jesús Esteban-Pérez, Alberto García-Redondo, Ammar Al-Chalabi, Ekaterina Rogaeva, Lorne Zinman, Lyle W. Ostrow, Nicholas J. Maragakis, Jeffrey D. Rothstein, Zachary Simmons, Johnathan Cooper-Knock, Alexis Brice, Stephen A. Goutman, Eva L. Feldman, Summer B. Gibson, Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip Van Damme, Wim Robberecht, Pietro Fratta, Mario Sabatelli, Christian Lunetta, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, William Camu, John Q. Trojanowski, Vivianna M. Van Deerlin, Robert H. Brown, Leonard H. van den Berg, Jan H. Veldink, Matthew B. Harms, Jonathan D. Glass, David J. Stone, Pentti Tienari, Vincenzo Silani, Adriano Chiò, Christopher E. Shaw, Bryan J. Traynor, John E. Landers, Isabella Simone, Giancarlo Logroscino, Ilaria Bartolomei, Maria Rita Murru, Emanuela Costantino, Carla Pani, Roberta Puddu, Carla Caredda, Valeria Piras, Stefania Tranquilli, Stefania Cuccu, Daniela Corongiu, Maurizio Melis, Antonio Milia, Francesco Marrosu, Maria Giovanna Marrosu, Gianluca Floris, Antonino Cannas, Gianluigi Mancardi, Paola Origone, Paola Mandich, Sebastiano Cavallaro, Kalliopi Marinou, Riccardo Sideri, Silvana Penco, Lorena Mosca, Giuseppe Lauria Pinter, Massimo Corbo, Paola Carrera, Nicola Fini, Antonio Fasano, Lucio Tremolizzo, Alessandro Arosio, Carlo Ferrarese, Gioacchino Tedeschi, Maria Rosaria Monsurrò, Giovanni Piccirillo, Cinzia Femiano, Anna Ticca, Enzo Ortu, Rossella Spataro, Tiziana Colletti, Marcella Zollino, Amelia Conte, Marco Luigetti, Serena Lattante, Marialuisa Santarelli, Antonio Petrucci, Maura Pugliatti, Angelo Pirisi, Leslie D. Parish, Patrizia Occhineri, Fabio Giannini, Claudia Ricci, Michele Benigni, Tea B. Cau, Daniela Loi, Cristina Moglia, Maura Brunetti, Marco Barberis, Gabriella Restagno, Federico Casale, Giuseppe Marrali, Giuseppe Fuda, Irene Ossola, Stefania Cammarosano, Antonio Canosa, Antonio Ilardi, Umberto Manera, Maurizio Grassano, Raffaella Tanel, Fabrizio Pisano, Neil A. Shneider, Stephen Goutman, Siddharthan Chandran, Suvankar Pal, George Manousakis, Stanley H. Appel, Ericka Simpson, Leo Wang, Summer Gibson, Richard Bedlack, David Lacomis, Dhruv Sareen, Alexander Sherman, Lucie Bruijn, Michelle Penny, Andrew S. Allen, Stanley Appel, Richard S. Bedlack, Braden E. Boone, Robert Brown, John P. Carulli, Alessandra Chesi, Wendy K. Chung, Elizabeth T. Cirulli, Gregory M. Cooper, Julien Couthouis, Aaron G. Day-Williams, Patrick A. Dion, Yujun Han, Sebastian D. Hayes, Angela L. Jones, Jonathan Keebler, Brian J. Krueger, Brittany N. Lasseigne, Shawn E. Levy, Yi-Fan Lu, Tom Maniatis, Slavé Petrovski, Alya R. Raphael, Zhong Ren, Katherine B. Sims, John F. Staropoli, Lindsay L. Waite, Quanli Wang, Jack R. Wimbish, Winnie W. Xin, Justin Kwan, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Noah Zaitlen, Gregory A. Cox, Steve Finkbeiner, Efthimios Dardiotis, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos A. Patsopoulos, Joshua Dubnau, Avindra Nath, Stacia Wyman, Alexander LeNail, Jenny Van Eyk, Stephan Züchner, Rebecca Schule, Jacob McCauley, Sumaira Hussain, Anne Cooley, Marielle Wallace, Christine Clayman, Richard Barohn, Jeffrey Statland, John Ravits, Andrea Swenson, Carlayne Jackson, Jaya Trivedi, Shaida Khan, Jonathan Katz, Liberty Jenkins, Ted Burns, Kelly Gwathmey, James Caress, Corey McMillan, Lauren Elman, Erik Pioro, Jeannine Heckmann, Yuen So, David Walk, Samuel Maiser, Jinghui Zhang, Fabiola De Marchi, Stefania Corti, Mauro Ceroni, Gabriele Siciliano, Massimiliano Filosto, Maurizio Inghilleri, Silvia Peverelli, Claudia Colombrita, Barbara Poletti, Luca Maderna, Roberto Del Bo, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Viviana Pensato, Barbara Castellotti, Vincent Meininger, Gérard Besson, Emmeline Lagrange, Pierre Clavelou, Nathalie Guy, Philippe Couratier, Patrick Vourch, Véronique Danel, Emilien Bernard, Gwendal Lemasson, Ahmad Al Kheifat, Peter Andersen, Adriano Chio, Jonathan Cooper-Knock, Annelot Dekker, Vivian Drory, Alberto Garcia Redondo, Marc Gotkine, Winston Hide, Alfredo Iacoangeli, Jonathan Glass, Kevin Kenna, Matthew Kiernan, John Landers, Russell McLaughlin, Jonathan Mill, Miguel Mitne Neto, Mattieu Moisse, Jesus Mora Pardina, Karen Morrison, Stephen Newhouse, Susana Pinto, Sara Pulit, Pamela Shaw, Chris Shaw, William Sproviero, Gijs Tazelaar, Philip van Damme, Leonard van den Berg, Rick van der Spek, Kristel van Eijk, Michael van Es, Joke van Vugt, Jan Veldink, Mayana Zatz, Denis C. Bauer, Natalie A. Twine, Department of Neurosciences, Pentti Tienari / Principal Investigator, Neurologian yksikkö, Research Programs Unit, Clinicum, Research Programme for Molecular Neurology, University of Helsinki, Medicum, Department of Pathology, HUS Neurocenter, Nicolas A., Kenna K.P., Renton A.E., Ticozzi N., Faghri F., Chia R., Dominov J.A., Kenna B.J., Nalls M.A., Keagle P., Rivera A.M., van Rheenen W., Murphy N.A., van Vugt J.J.F.A., Geiger J.T., Van der Spek R.A., Pliner H.A., Shankaracharya, Smith B.N., Marangi G., Topp S.D., Abramzon Y., Gkazi A.S., Eicher J.D., Kenna A., Logullo F.O., Simone I.L., Logroscino G., Salvi F., Bartolomei I., Borghero G., Murru M.R., Costantino E., Pani C., Puddu R., Caredda C., Piras V., Tranquilli S., Cuccu S., Corongiu D., Melis M., Milia A., Marrosu F., Marrosu M.G., Floris G., Cannas A., Capasso M., Caponnetto C., Mancardi G., Origone P., Mandich P., Conforti F.L., Cavallaro S., Mora G., Marinou K., Sideri R., Penco S., Mosca L., Lunetta C., Pinter G.L., Corbo M., Riva N., Carrera P., Volanti P., Mandrioli J., Fini N., Fasano A., Tremolizzo L., Arosio A., Ferrarese C., Trojsi F., Tedeschi G., Monsurro M.R., Piccirillo G., Femiano C., Ticca A., Ortu E., La Bella V., Spataro R., Colletti T., Sabatelli M., Zollino M., Conte A., Luigetti M., Lattante S., Santarelli M., Petrucci A., Pugliatti M., Pirisi A., Parish L.D., Occhineri P., Giannini F., Battistini S., Ricci C., Benigni M., Cau T.B., Loi D., Calvo A., Moglia C., Brunetti M., Barberis M., Restagno G., Casale F., Marrali G., Fuda G., Ossola I., Cammarosano S., Canosa A., Ilardi A., Manera U., Grassano M., Tanel R., Pisano F., Mazzini L., Messina S., D'Alfonso S., Corrado L., Ferrucci L., Harms M.B., Goldstein D.B., Shneider N.A., Goutman S.A., Simmons Z., Miller T.M., Chandran S., Pal S., Manousakis G., Appel S.H., Simpson E., Wang L., Baloh R.H., Gibson S.B., Bedlack R., Lacomis D., Sareen D., Sherman A., Bruijn L., Penny M., Moreno C.D.A.M., Kamalakaran S., Allen A.S., Boone B.E., Brown R.H., Carulli J.P., Chesi A., Chung W.K., Cirulli E.T., Cooper G.M., Couthouis J., Day-Williams A.G., Dion P.A., Gitler A.D., Glass J.D., Han Y., Harris T., Hayes S.D., Jones A.L., Keebler J., Krueger B.J., Lasseigne B.N., Levy S.E., Lu Y.-F., Maniatis T., McKenna-Yasek D., Myers R.M., Petrovski S., Pulst S.M., Raphael A.R., Ravits J.M., Ren Z., Rouleau G.A., Sapp P.C., Sims K.B., Staropoli J.F., Waite L.L., Wang Q., Wimbish J.R., Xin W.W., Phatnani H., Kwan J., Broach J., Arcila-Londono X., Lee E.B., Van Deerlin V.M., Fraenkel E., Ostrow L.W., Baas F., Zaitlen N., Berry J.D., Malaspina A., Fratta P., Cox G.A., Thompson L.M., Finkbeiner S., Dardiotis E., Hornstein E., MacGowan D.J.L., Heiman-Patterson T., Hammell M.G., Patsopoulos N.A., Dubnau J., Nath A., Musunuri R.L., Evani U.S., Abhyankar A., Zody M.C., Kaye J., Wyman S.K., LeNail A., Lima L., Rothstein J.D., Svendsen C.N., Van Eyk J.E., Maragakis N.J., Kolb S.J., Cudkowicz M., Baxi E., Benatar M., Taylor J.P., Wu G., Rampersaud E., Wuu J., Rademakers R., Zuchner S., Schule R., McCauley J., Hussain S., Cooley A., Wallace M., Clayman C., Barohn R., Statland J., Swenson A., Jackson C., Trivedi J., Khan S., Katz J., Jenkins L., Burns T., Gwathmey K., Caress J., McMillan C., Elman L., Pioro E.P., Heckmann J., So Y., Walk D., Maiser S., Zhang J., Silani V., Gellera C., Ratti A., Taroni F., Lauria G., Verde F., Fogh I., Tiloca C., Comi G.P., Soraru G., Cereda C., De Marchi F., Corti S., Ceroni M., Siciliano G., Filosto M., Inghilleri M., Peverelli S., Colombrita C., Poletti B., Maderna L., Del Bo R., Gagliardi S., Querin G., Bertolin C., Pensato V., Castellotti B., Camu W., Mouzat K., Lumbroso S., Corcia P., Meininger V., Besson G., Lagrange E., Clavelou P., Guy N., Couratier P., Vourch P., Danel V., Bernard E., Lemasson G., Laaksovirta H., Myllykangas L., Jansson L., Valori M., Ealing J., Hamdalla H., Rollinson S., Pickering-Brown S., Orrell R.W., Sidle K.C., Hardy J., Singleton A.B., Johnson J.O., Arepalli S., Polak M., Asress S., Al-Sarraj S., King A., Troakes C., Vance C., de Belleroche J., ten Asbroek A.L.M.A., Munoz-Blanco J.L., Hernandez D.G., Ding J., Gibbs J.R., Scholz S.W., Floeter M.K., Campbell R.H., Landi F., Bowser R., Kirby J., Pamphlett R., Gerhard G., Dunckley T.L., Brady C.B., Kowall N.W., Troncoso J.C., Le Ber I., Heiman-Patterson T.D., Kamel F., Van Den Bosch L., Strom T.M., Meitinger T., Shatunov A., Van Eijk K.R., de Carvalho M., Kooyman M., Middelkoop B., Moisse M., McLaughlin R.L., Van Es M.A., Weber M., Boylan K.B., Van Blitterswijk M., Morrison K.E., Basak A.N., Mora J.S., Drory V.E., Shaw P.J., Turner M.R., Talbot K., Hardiman O., Williams K.L., Fifita J.A., Nicholson G.A., Blair I.P., Esteban-Perez J., Garcia-Redondo A., Al-Chalabi A., Al Kheifat A., Andersen P.M., Chio A., Cooper-Knock J., Dekker A., Redondo A.G., Gotkine M., Hide W., Iacoangeli A., Kiernan M., Landers J.E., Mill J., Neto M.M., Pardina J.M., Newhouse S., Pinto S., Pulit S., Robberecht W., Shaw C., Sproviero W., Tazelaar G., Van Damme P., van den Berg L.H., van Vugt J., Veldink J.H., Zatz M., Bauer D.C., Twine N.A., Rogaeva E., Zinman L., Brice A., Feldman E.L., Ludolph A.C., Weishaupt J.H., Trojanowski J.Q., Stone D.J., Tienari P., Shaw C.E., Traynor B.J., ITALSGEN Consortium, Genomic Translation ALS Care GTAC, ALS Sequencing Consortium, NYGC ALS Consortium, Answer ALS Fdn, Clinical Res ALS Related Disorders, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consor, Medical Research Council (MRC), ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Università cattolica del Sacro Cuore [Roma] (Unicatt), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Lunar and Planetary Laboratory [Tucson] (LPL), University of Arizona, Università degli studi di Torino (UNITO), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), New York Genome Center [New York], New York Genome Center, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), St Jude Children's Research Hospital, Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University College of London [London] (UCL), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), King‘s College London, University of New Haven [Connecticut], Princeton University, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), University Medical Center [Utrecht], Deutsches Forschungszentrum für Künstliche Intelligenz GmbH = German Research Center for Artificial Intelligence (DFKI), Mayo Clinic [Jacksonville], Trinity College Dublin, Maurice Wohl Clinical Neuroscience Institut, Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Repositório da Universidade de Lisboa, Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P, Renton, Alan E, Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A, Kenna, Brendan J, Nalls, Mike A, Keagle, Pamela, Rivera, Alberto M, van Rheenen, Wouter, Murphy, Natalie A, van Vugt, Joke J F A, Geiger, Joshua T, Van der Spek, Rick A, Pliner, Hannah A, Shankaracharya, Null, Smith, Bradley N, Marangi, Giuseppe, Topp, Simon D, Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D, Kenna, Aoife, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L, Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L, Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O, D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Logullo, Fo, Murru, Mr, Marrosu, Mg, Conforti, Fl, Pinter, Gl, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Parish, Ld, Cau, Tb, Moreno, Cristiane de Araujo Martin, Kamalakaran, Sitharthan, Goldstein, David B, Gitler, Aaron D, Harris, Tim, Myers, Richard M, Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K, Lenail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N, Thompson, Leslie M, Van Eyk, Jennifer E, Berry, James D, Miller, Timothy M, Kolb, Stephen J, Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P, Sorarù, Gianni, Cereda, Cristina, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W, Sidle, Katie C, Malaspina, Andrea, Hardy, John, Singleton, Andrew B, Johnson, Janel O, Arepalli, Sampath, Sapp, Peter C, McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, Baas, Frank, Ten Asbroek, Anneloor L M A, Muñoz-Blanco, José Lui, Hernandez, Dena G, Ding, Jinhui, Gibbs, J Raphael, Scholz, Sonja W, Floeter, Mary Kay, Campbell, Roy H, Landi, Francesco, Bowser, Robert, Pulst, Stefan M, Ravits, John M, Macgowan, Daniel J L, Kirby, Janine, Pioro, Erik P, Pamphlett, Roger, Broach, Jame, Gerhard, Glenn, Dunckley, Travis L, Brady, Christopher B, Kowall, Neil W, Troncoso, Juan C, Le Ber, Isabelle, Mouzat, Kevin, Lumbroso, Serge, Heiman-Patterson, Terry D, Kamel, Freya, Van Den Bosch, Ludo, Baloh, Robert H, Strom, Tim M, Meitinger, Thoma, Shatunov, Aleksey, Van Eijk, Kristel R, de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Ba, Moisse, Matthieu, Mclaughlin, Russell L, Van Es, Michael A, Weber, Marku, Boylan, Kevin B, Van Blitterswijk, Marka, Rademakers, Rosa, Morrison, Karen E, Basak, A Nazli, Mora, Jesús S, Drory, Vivian E, Shaw, Pamela J, Turner, Martin R, Talbot, Kevin, Hardiman, Orla, Williams, Kelly L, Fifita, Jennifer A, Nicholson, Garth A, Blair, Ian P, Rouleau, Guy A, Esteban-Pérez, Jesú, García-Redondo, Alberto, Al-Chalabi, Ammar, Rogaeva, Ekaterina, Zinman, Lorne, Ostrow, Lyle W, Maragakis, Nicholas J, Rothstein, Jeffrey D, Simmons, Zachary, Cooper-Knock, Johnathan, Brice, Alexi, Goutman, Stephen A, Feldman, Eva L, Gibson, Summer B, Taroni, Franco, Ratti, Antonia, Gellera, Cinzia, Van Damme, Philip, Robberecht, Wim, Fratta, Pietro, Sabatelli, Mario, Lunetta, Christian, Ludolph, Albert C, Andersen, Peter M, Weishaupt, Jochen H, Camu, William, Trojanowski, John Q, Van Deerlin, Vivianna M, Brown, Robert H, van den Berg, Leonard H, Veldink, Jan H, Harms, Matthew B, Glass, Jonathan D, Stone, David J, Tienari, Pentti, Silani, Vincenzo, Chiò, Adriano, Shaw, Christopher E, Traynor, Bryan J, Landers, John E, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
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Male ,Als gene ,Genome-wide association study ,FAMILIAL ALS ,ALS ,axonal transport ,cargo ,GWAS ,KIF5A ,WES ,WGS ,0302 clinical medicine ,80 and over ,Psychology ,Aetiology ,Aged, 80 and over ,0303 health sciences ,French ALS Consortium ,Kinesin ,KINESIN HEAVY-CHAIN ,Cognitive Sciences ,Human ,Hereditary spastic paraplegia ,Neuroscience(all) ,Single-nucleotide polymorphism ,TARGETED DISRUPTION ,Article ,03 medical and health sciences ,Genetics ,Humans ,Amino Acid Sequence ,Loss function ,Aged ,HEXANUCLEOTIDE REPEAT ,Neuroscience (all) ,MUTATIONS ,Amyotrophic Lateral Sclerosis ,3112 Neurosciences ,1702 Cognitive Science ,medicine.disease ,ITALSGEN Consortium ,Answer ALS Foundation ,030104 developmental biology ,ALS Sequencing Consortium ,Human medicine ,1109 Neurosciences ,030217 neurology & neurosurgery ,0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Kinesins ,Neurodegenerative ,Genetic analysis ,Genome ,AMYOTROPHIC-LATERAL-SCLEROSIS ,3124 Neurology and psychiatry ,Cohort Studies ,Pathogenesis ,Loss of Function Mutation ,Missense mutation ,2.1 Biological and endogenous factors ,Amyotrophic lateral sclerosis ,NYGC ALS Consortium ,General Neuroscience ,ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS ,Middle Aged ,Phenotype ,Settore MED/26 - NEUROLOGIA ,Neurological ,Project MinE ALS Sequencing Consortium ,Female ,Adult ,Biology ,GENOTYPE IMPUTATION ,Genome-Wide Association Study ,Young Adult ,NO ,Rare Diseases ,medicine ,SLAGEN Consortium ,Gene ,030304 developmental biology ,Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium ,Neurology & Neurosurgery ,Human Genome ,Neurosciences ,AXONAL-TRANSPORT ,Brain Disorders ,Family member ,DNA-DAMAGE ,MOTOR-NEURONS ,3111 Biomedicine ,Cohort Studie ,Genomic Translation for ALS Care (GTAC) Consortium ,Amyotrophic Lateral Sclerosi - Abstract
© 2018 Elsevier Inc., To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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- 2018
173. Chromosome 9p21 in amyotrophic lateral sclerosis: the plot thickens
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Daoud, Hussein, Belzil, Véronique, Dion, Patrick A, Rouleau, Guy A, Shatunov, Aleksey, Mok, Kin, Newhouse, Stephen, Weale, Michael E, Smith, Bradley, Vance, Caroline, Johnson, Lauren, Veldink, Jan H, van Es, Michael A, van den Berg, Leonard H, Robberecht, Wim, Van Damme, Philip, Hardiman, Orla, Farmer, Anne E, Lewis, Cathryn M, and Butler, Amy W
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AMYOTROPHIC lateral sclerosis , *CHROMOSOMES , *COMPARATIVE studies , *GENETIC polymorphisms , *INTERNATIONAL relations , *LONGITUDINAL method , *RESEARCH methodology , *MEDICAL cooperation , *RESEARCH , *RESEARCH funding , *EVALUATION research , *CASE-control method , *FRONTOTEMPORAL dementia , *SEQUENCE analysis - Abstract
Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons that results in progressive weakness and death from respiratory failure, commonly within about 3 years. Previous studies have shown association of a locus on chromosome 9p with ALS and linkage with ALS-frontotemporal dementia. We aimed to test whether this genomic region is also associated with ALS in an independent set of UK samples, and to identify risk factors associated with ALS in a further genome-wide association study that combined data from the independent analysis with those from other countries.Methods: We collected samples from patients with sporadic ALS from 20 UK hospitals and obtained UK control samples from the control groups of the Depression Case Control study, the Bipolar Affective Case Control Study, and the British 1958 birth cohort DNA collection. Genotyping of DNA in this independent analysis was done with Illumina HumanHap550 BeadChips. We then undertook a joint genome-wide analysis that combined data from the independent set with published data from the UK, USA, Netherlands, Ireland, Italy, France, Sweden, and Belgium. The threshold for significance was p=0·05 in the independent analysis, because we were interested in replicating a small number of previously reported associations, whereas the Bonferroni-corrected threshold for significance in the joint analysis was p=2·20×10(-7)Findings: After quality control, samples were available from 599 patients and 4144 control individuals in the independent set. In this analysis, two single nucleotide polymorphisms in a locus on chromosome 9p21.2 were associated with ALS: rs3849942 (p=2·22×10(-6); odds ratio [OR] 1·39, 95% CI 1·21-1·59) and rs2814707 (p=3·32×10(-6); 1·38, 1·20-1·58). In the joint analysis, which included samples from 4312 patients with ALS and 8425 control individuals, rs3849942 (p=4·64×10(-10); OR 1·22, 95% CI 1·15-1·30) and rs2814707 (p=4·72×10(-10); 1·22, 1·15-1·30) were associated with ALS.Interpretation: We have found strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent GWAS of ALS and linkage studies of ALS-frontotemporal dementia. Our findings together with these earlier findings suggest that genetic variation at this locus on chromosome 9 causes sporadic ALS and familial ALS-frontotemporal dementia. Resequencing studies and then functional analysis should be done to identify the defective gene. [ABSTRACT FROM AUTHOR]- Published
- 2010
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174. 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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175. 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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176. 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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177. 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
- Abstract
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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178. 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
- Subjects
- Humans, United States, Genetic Predisposition to Disease genetics, C9orf72 Protein genetics, Superoxide Dismutase-1 genetics, Amyotrophic Lateral Sclerosis genetics
- Abstract
With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), there is a surge in gene testing for this disease. Although there is ample experience with gene testing for C9orf72, SOD1, FUS and TARDBP in familial ALS, large studies exploring genetic variation in all ALS-associated genes in sporadic ALS (sALS) are still scarce. Gene testing in a diagnostic setting is challenging, given the complex genetic architecture of sALS, for which there are genetic variants with large and small effect sizes. Guidelines for the interpretation of genetic variants in gene panels and for counselling of patients are lacking. We aimed to provide a thorough characterization of genetic variability in ALS genes by applying the American College of Medical Genetics and Genomics (ACMG) criteria on whole genome sequencing data from a large cohort of 6013 sporadic ALS patients and 2411 matched controls from Project MinE. We studied genetic variation in 90 ALS-associated genes and applied customized ACMG-criteria to identify pathogenic and likely pathogenic variants. Variants of unknown significance were collected as well. In addition, we determined the length of repeat expansions in C9orf72, ATXN1, ATXN2 and NIPA1 using the ExpansionHunter tool. We found C9orf72 repeat expansions in 5.21% of sALS patients. In 50 ALS-associated genes, we did not identify any pathogenic or likely pathogenic variants. In 5.89%, a pathogenic or likely pathogenic variant was found, most commonly in SOD1, TARDBP, FUS, NEK1, OPTN or TBK1. Significantly more cases carried at least one pathogenic or likely pathogenic variant compared to controls (odds ratio 1.75; P-value 1.64 × 10-5). Isolated risk factors in ATXN1, ATXN2, NIPA1 and/or UNC13A were detected in 17.33% of cases. In 71.83%, we did not find any genetic clues. A combination of variants was found in 2.88%. This study provides an inventory of pathogenic and likely pathogenic genetic variation in a large cohort of sALS patients. Overall, we 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.)
- Published
- 2023
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179. 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
- Abstract
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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180. 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.)
- Published
- 2023
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181. 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
- Subjects
- 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
- Abstract
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.)
- Published
- 2023
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182. 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
- Abstract
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.)
- Published
- 2023
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183. 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.)
- Published
- 2023
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184. 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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185. 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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- 2022
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186. 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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187. 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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- 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
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons., (© 2021. The Author(s).)
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- 2021
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188. 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
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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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189. 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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190. 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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191. Is it accurate to classify ALS as a neuromuscular disorder?
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van Es MA, Goedee HS, Westeneng HJ, Nijboer TCW, and van den Berg LH
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- Humans, Amyotrophic Lateral Sclerosis classification, Neurodegenerative Diseases classification, Neuromuscular Diseases classification
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Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by the progressive loss of upper and lower motor neurons. ALS has traditionally been classified within the domain of neuromuscular diseases, which are a unique spectrum of disorders that predominantly affect the peripheral nervous system. However, over the past decades compounding evidence has emerged that there is extensive involvement of the central nervous system. Therefore, one can question whether it remains accurate to classify ALS as a neuromuscular disorder., Areas Covered: In this review, the authors sought to discuss current approaches toward disease classification and how we should classify ALS based on novel insights from clinical, imaging, pathophysiological, neuropathological and genetic studies., Expert Opinion: ALS exhibits the cardinal features of a neurodegenerative disease. Therefore, classifying ALS as a neuromuscular disease in the strict sense has become untenable. Diagnosing ALS however does require significant neuromuscular expertise and therefore neuromuscular specialists remain best equipped to evaluate this category of patients. Designating motor neuron diseases as a separate category in the ICD-11 is justified and adequately deals with this issue. However, to drive effective therapy development the fields of motor neuron disease and neurodegenerative disorders must come together.
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- 2020
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192. Multimodal longitudinal study of structural brain involvement in amyotrophic lateral sclerosis.
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van der Burgh HK, Westeneng HJ, Walhout R, van Veenhuijzen K, Tan HHG, Meier JM, Bakker LA, Hendrikse J, van Es MA, Veldink JH, van den Heuvel MP, and van den Berg LH
- Subjects
- Aged, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis pathology, Behavior, Brain pathology, C9orf72 Protein genetics, Cognition, Cross-Sectional Studies, Diffusion Magnetic Resonance Imaging, Disease Progression, Female, Gray Matter diagnostic imaging, Gray Matter pathology, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Multimodal Imaging, Mutation, Prospective Studies, White Matter diagnostic imaging, White Matter pathology, Amyotrophic Lateral Sclerosis diagnostic imaging, Brain diagnostic imaging
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Objective: To understand the progressive nature of amyotrophic lateral sclerosis (ALS) by investigating differential brain patterns of gray and white matter involvement in clinically or genetically defined subgroups of patients using cross-sectional, longitudinal, and multimodal MRI., Methods: We assessed cortical thickness, subcortical volumes, and white matter connectivity from T1-weighted and diffusion-weighted MRI in 292 patients with ALS (follow-up: n = 150) and 156 controls (follow-up: n = 72). Linear mixed-effects models were used to assess changes in structural brain measurements over time in patients compared to controls., Results: Patients with a C9orf72 mutation (n = 24) showed widespread gray and white matter involvement at baseline, and extensive loss of white matter integrity in the connectome over time. In C9orf72 -negative patients, we detected cortical thinning of motor and frontotemporal regions, and loss of white matter integrity of connections linked to the motor cortex. Patients with spinal onset displayed widespread white matter involvement at baseline and gray matter atrophy over time, whereas patients with bulbar onset started out with prominent gray matter involvement. Patients with unaffected cognition or behavior displayed predominantly motor system involvement, while widespread cerebral changes, including frontotemporal regions with progressive white matter involvement over time, were associated with impaired behavior or cognition. Progressive loss of gray and white matter integrity typically occurred in patients with shorter disease durations (<13 months), independent of progression rate., Conclusions: Heterogeneity of phenotype and C9orf72 genotype relates to distinct patterns of cerebral degeneration. We demonstrate that imaging studies have the potential to monitor disease progression and early intervention may be required to limit cerebral degeneration., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2020
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193. ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization.
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Tazelaar GHP, Boeynaems S, De Decker M, van Vugt JJFA, Kool L, Goedee HS, McLaughlin RL, Sproviero W, Iacoangeli A, Moisse M, Jacquemyn M, Daelemans D, Dekker AM, van der Spek RA, Westeneng HJ, Kenna KP, Assialioui A, Da Silva N, Povedano M, Pardina JSM, Hardiman O, Salachas F, Millecamps S, Vourc'h P, Corcia P, Couratier P, Morrison KE, Shaw PJ, Shaw CE, Pasterkamp RJ, Landers JE, Van Den Bosch L, Robberecht W, Al-Chalabi A, van den Berg LH, Van Damme P, Veldink JH, and van Es MA
- Abstract
Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in C9orf72 , polyglutamine expansions in ATXN2 and polyalanine expansions in NIPA1 . Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in ATXN1 , suggested a similar disease association for the repeat expansion in ATXN1 . We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate ATXN1 repeat expansions and amyotrophic lateral sclerosis ( P = 3.33 × 10
-7 ). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in Drosophila , further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)- Published
- 2020
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194. Pharmacogenetic interactions in amyotrophic lateral sclerosis: a step closer to a cure?
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van Eijk RPA, Eijkemans MJC, Nikolakopoulos S, Jansen MD, Westeneng HJ, van Eijk KR, van der Spek RAA, van Vugt JJFA, Piepers S, Groeneveld GJ, Veldink JH, van den Berg LH, and van Es MA
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- Amyotrophic Lateral Sclerosis diagnosis, Amyotrophic Lateral Sclerosis epidemiology, Double-Blind Method, Humans, Mutation genetics, Netherlands epidemiology, Pharmacogenomic Testing methods, Amyotrophic Lateral Sclerosis genetics, C9orf72 Protein genetics, Epistasis, Genetic genetics, Myelin Proteins genetics, Nerve Tissue Proteins genetics, Pharmacogenetics methods
- Abstract
Genetic mutations related to amyotrophic lateral sclerosis (ALS) act through distinct pathophysiological pathways, which may lead to varying treatment responses. Here we assess the genetic interaction between C9orf72, UNC13A, and MOBP with creatine and valproic acid treatment in two clinical trials. Genotypic data was available for 309 of the 338 participants (91.4%). The UNC13A genotype affected mortality (p = 0.012), whereas C9orf72 repeat-expansion carriers exhibited a faster rate of decline in overall (p = 0.051) and bulbar functioning (p = 0.005). A dose-response pharmacogenetic interaction was identified between creatine and the A allele of the MOBP genotype (p = 0.027), suggesting a qualitative interaction in a recessive model (HR 3.96, p = 0.015). Not taking genetic information into account may mask evidence of response to treatment or be an unrecognized source of bias. Incorporating genetic data could help investigators to identify critical treatment clues in patients with ALS.
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- 2020
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195. KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.
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Pennings M, Schouten MI, van Gaalen J, Meijer RPP, de Bot ST, Kriek M, Saris CGJ, van den Berg LH, van Es MA, Zuidgeest DMH, Elting MW, van de Kamp JM, van Spaendonck-Zwarts KY, Die-Smulders C, Brilstra EH, Verschuuren CC, de Vries BBA, Bruijn J, Sofou K, Duijkers FA, Jaeger B, Schieving JH, van de Warrenburg BP, and Kamsteeg EJ
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- Adolescent, Adult, Child, Child, Preschool, Female, Genes, Dominant, Humans, Infant, Kinesins chemistry, Male, Middle Aged, Mutation, Missense, Pedigree, Protein Domains, Spastic Paraplegia, Hereditary pathology, Kinesins genetics, Spastic Paraplegia, Hereditary genetics
- Abstract
Variants in the KIF1A gene can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal (de novo) dominant mental retardation type 9. More recently, variants in KIF1A have also been described in a few cases with autosomal dominant spastic paraplegia. Here, we describe 20 KIF1A variants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly 'pure' spastic paraplegia. In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0-57 years). Segregation analyses showed a de novo occurrence in seven cases, and a dominant inheritance pattern in 11 families. The motor domain of KIF1A is a hotspot for disease causing variants in autosomal dominant spastic paraplegia, similar to mental retardation type 9 and recessive spastic paraplegia type 30. However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families. Finally, three missense variants were outside the motor domain and need further characterization. In conclusion, KIF1A variants are a frequent cause of autosomal dominant spastic paraplegia in our cohort (6-7%). The identification of KIF1A loss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic paraplegia.
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- 2020
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196. Prospective natural history study of C9orf72 ALS clinical characteristics and biomarkers.
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Cammack AJ, Atassi N, Hyman T, van den Berg LH, Harms M, Baloh RH, Brown RH, van Es MA, Veldink JH, de Vries BS, Rothstein JD, Drain C, Jockel-Balsarotti J, Malcolm A, Boodram S, Salter A, Wightman N, Yu H, Sherman AV, Esparza TJ, McKenna-Yasek D, Owegi MA, Douthwright C, McCampbell A, Ferguson T, Cruchaga C, Cudkowicz M, and Miller TM
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- Age of Onset, Amyotrophic Lateral Sclerosis epidemiology, Biomarkers blood, Biomarkers cerebrospinal fluid, Biomarkers urine, DNA Repeat Expansion, Female, Follow-Up Studies, Heterozygote, Humans, Longitudinal Studies, Male, Middle Aged, Prospective Studies, Retrospective Studies, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism, C9orf72 Protein genetics
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Objective: To define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies., Methods: We prospectively collected clinical and demographic data from 116 symptomatic C9ALS and 12 non-amyotrophic lateral sclerosis (ALS) full expansion carriers across 7 institutions in the United States and the Netherlands. In addition, we collected blood samples for DNA repeat size assessment, CSF samples for biomarker identification, and autopsy samples for dipeptide repeat protein (DPR) size determination. Finally, we collected retrospective clinical data via chart review from 208 individuals with C9ALS and 450 individuals with singleton ALS., Results: The mean age at onset in the symptomatic prospective cohort was 57.9 ± 8.3 years, and median duration of survival after onset was 36.9 months. The monthly change was -1.8 ± 1.7 for ALS Functional Rating Scale-Revised and -1.4% ± 3.24% of predicted for slow vital capacity. In blood DNA, we found that G
4 C2 repeat size correlates positively with age. In CSF, we observed that concentrations of poly(GP) negatively correlate with DNA expansion size but do not correlate with measures of disease progression. Finally, we found that size of poly(GP) dipeptides in the brain can reach large sizes similar to that of their DNA repeat derivatives., Conclusions: We present a thorough investigation of C9ALS natural history, providing the basis for C9ALS clinical trial design. We found that clinical features of this genetic subset are less variant than in singleton ALS. In addition, we identified important correlations of C9ALS patient pathologies with clinical and demographic data., (© 2019 American Academy of Neurology.)- Published
- 2019
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197. Cognitive and behavioural changes in PLS and PMA:challenging the concept of restricted phenotypes.
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de Vries BS, Rustemeijer LMM, Bakker LA, Schröder CD, Veldink JH, van den Berg LH, Nijboer TCW, and van Es MA
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- Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis diagnosis, Cognitive Dysfunction diagnosis, Female, Humans, Male, Middle Aged, Neuropsychological Tests, Phenotype, Retrospective Studies, Amyotrophic Lateral Sclerosis psychology, Cognitive Dysfunction epidemiology, Mental Disorders epidemiology, Motor Neuron Disease psychology, Muscular Atrophy, Spinal psychology
- Abstract
Objectives: Cognitive and behavioural changes within the spectrum of frontotemporal dementia (FTD) are observed frequently in patients with amyotrophic lateral sclerosis (ALS). Whether these changes also occur in other forms of motor neuron disease (MND) is not well studied. We therefore systemically screened a large cohort of patients with primary lateral sclerosis (PLS) and progressive muscular atrophy (PMA) for cognitive and behavioural changes, and subsequently compared our findings with a cohort of patients with ALS., Methods: Using a set of screening instruments (Edinburgh Cognitive and Behavioural ALS Screen, ALS and Frontotemporal Dementia Questionnaire, Frontal Assessment Battery, and Hospital Anxiety and Depression Scale), the presence of cognitive and behavioural changes as well as anxiety and depression in 277 patients with ALS, 75 patients with PLS and 143 patients with PMA was evaluated retrospectively., Results: We found a high frequency of cognitive and behavioural abnormalities with similar profiles in all three groups. Subjects with behavioural variant FTD were identified in all groups., Conclusions: The percentage of patients with PLS and PMA with cognitive dysfunction was similar to patients with ALS, emphasising the importance for cognitive screening as part of routine clinical care in all three patient groups. With a similar cognitive profile, in line with genetic and clinical overlap between the MNDs, the view of PLS as an MND exclusively affecting upper motor neurons and PMA exclusively affecting lower motor neurons cannot be held. Therefore, our findings are in contrast to the recently revised El Escorial criteria of 2015, where PLS and PMA are described as restricted phenotypes. Our study favours a view of PLS and PMA as multidomain diseases similar to ALS., Competing Interests: Competing interests: MAvE serves on the UK Motor Neurone Disease Association Biomedical Research Advisory Panel, has consulted for Biogen and has received travel grants from Shire (formerly Baxalta). LHvdB reports grants from Netherlands ALS Foundation, grants from Prinses Beatrix Spierfonds, grants from Netherlands Organization for Health Research and Development (Vici scheme), and grants from European Community’s Health Seventh Framework Programme (FP7/2007-2013) (grant agreement no 259867), during the conduct of the study; and personal fees from Baxter for scientific advisory board and travel grant, and personal fees from Scientific Advisory Board, Biogen Idec, outside the submitted work. The other authors declare that they have no conflict of interest., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2019
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198. Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort.
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Tazelaar GHP, Dekker AM, van Vugt JJFA, van der Spek RA, Westeneng HJ, Kool LJBG, Kenna KP, van Rheenen W, Pulit SL, McLaughlin RL, Sproviero W, Iacoangeli A, Hübers A, Brenner D, Morrison KE, Shaw PJ, Shaw CE, Panadés MP, Mora Pardina JS, Glass JD, Hardiman O, Al-Chalabi A, van Damme P, Robberecht W, Landers JE, Ludolph AC, Weishaupt JH, van den Berg LH, Veldink JH, and van Es MA
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- Cohort Studies, Female, Humans, Internationality, Logistic Models, Male, Meta-Analysis as Topic, Peptides genetics, Amyotrophic Lateral Sclerosis genetics, DNA Repeat Expansion genetics, Genetic Association Studies, Membrane Proteins genetics
- Abstract
NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome 1) mutations are known to cause hereditary spastic paraplegia type 6, a neurodegenerative disease that phenotypically overlaps to some extent with amyotrophic lateral sclerosis (ALS). Previously, a genomewide screen for copy number variants found an association with rare deletions in NIPA1 and ALS, and subsequent genetic analyses revealed that long (or expanded) polyalanine repeats in NIPA1 convey increased ALS susceptibility. We set out to perform a large-scale replication study to further investigate the role of NIPA1 polyalanine expansions with ALS, in which we characterized NIPA1 repeat size in an independent international cohort of 3955 patients with ALS and 2276 unaffected controls and combined our results with previous reports. Meta-analysis on a total of 6245 patients with ALS and 5051 controls showed an overall increased risk of ALS in those with expanded (>8) GCG repeat length (odds ratio = 1.50, p = 3.8×10
-5 ). Together with previous reports, these findings provide evidence for an association of an expanded polyalanine repeat in NIPA1 and ALS., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2019
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199. Prognosis for patients with amyotrophic lateral sclerosis: development and validation of a personalised prediction model.
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Westeneng HJ, Debray TPA, Visser AE, van Eijk RPA, Rooney JPK, Calvo A, Martin S, McDermott CJ, Thompson AG, Pinto S, Kobeleva X, Rosenbohm A, Stubendorff B, Sommer H, Middelkoop BM, Dekker AM, van Vugt JJFA, van Rheenen W, Vajda A, Heverin M, Kazoka M, Hollinger H, Gromicho M, Körner S, Ringer TM, Rödiger A, Gunkel A, Shaw CE, Bredenoord AL, van Es MA, Corcia P, Couratier P, Weber M, Grosskreutz J, Ludolph AC, Petri S, de Carvalho M, Van Damme P, Talbot K, Turner MR, Shaw PJ, Al-Chalabi A, Chiò A, Hardiman O, Moons KGM, Veldink JH, and van den Berg LH
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- Aged, Amyotrophic Lateral Sclerosis classification, Amyotrophic Lateral Sclerosis physiopathology, Europe, Female, Follow-Up Studies, Humans, Male, Middle Aged, Precision Medicine, Prognosis, Reproducibility of Results, Amyotrophic Lateral Sclerosis diagnosis, Disease Progression, Models, Neurological, Severity of Illness Index, Survival Analysis
- Abstract
Background: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, fatal motor neuron disease with a variable natural history. There are no accurate models that predict the disease course and outcomes, which complicates risk assessment and counselling for individual patients, stratification of patients for trials, and timing of interventions. We therefore aimed to develop and validate a model for predicting a composite survival endpoint for individual patients with ALS., Methods: We obtained data for patients from 14 specialised ALS centres (each one designated as a cohort) in Belgium, France, the Netherlands, Germany, Ireland, Italy, Portugal, Switzerland, and the UK. All patients were diagnosed in the centres after excluding other diagnoses and classified according to revised El Escorial criteria. We assessed 16 patient characteristics as potential predictors of a composite survival outcome (time between onset of symptoms and non-invasive ventilation for more than 23 h per day, tracheostomy, or death) and applied backward elimination with bootstrapping in the largest population-based dataset for predictor selection. Data were gathered on the day of diagnosis or as soon as possible thereafter. Predictors that were selected in more than 70% of the bootstrap resamples were used to develop a multivariable Royston-Parmar model for predicting the composite survival outcome in individual patients. We assessed the generalisability of the model by estimating heterogeneity of predictive accuracy across external populations (ie, populations not used to develop the model) using internal-external cross-validation, and quantified the discrimination using the concordance (c) statistic (area under the receiver operator characteristic curve) and calibration using a calibration slope., Findings: Data were collected between Jan 1, 1992, and Sept 22, 2016 (the largest data-set included data from 1936 patients). The median follow-up time was 97·5 months (IQR 52·9-168·5). Eight candidate predictors entered the prediction model: bulbar versus non-bulbar onset (univariable hazard ratio [HR] 1·71, 95% CI 1·63-1·79), age at onset (1·03, 1·03-1·03), definite versus probable or possible ALS (1·47, 1·39-1·55), diagnostic delay (0·52, 0·51-0·53), forced vital capacity (HR 0·99, 0·99-0·99), progression rate (6·33, 5·92-6·76), frontotemporal dementia (1·34, 1·20-1·50), and presence of a C9orf72 repeat expansion (1·45, 1·31-1·61), all p<0·0001. The c statistic for external predictive accuracy of the model was 0·78 (95% CI 0·77-0·80; 95% prediction interval [PI] 0·74-0·82) and the calibration slope was 1·01 (95% CI 0·95-1·07; 95% PI 0·83-1·18). The model was used to define five groups with distinct median predicted (SE) and observed (SE) times in months from symptom onset to the composite survival outcome: very short 17·7 (0·20), 16·5 (0·23); short 25·3 (0·06), 25·2 (0·35); intermediate 32·2 (0·09), 32·8 (0·46); long 43·7 (0·21), 44·6 (0·74); and very long 91·0 (1·84), 85·6 (1·96)., Interpretation: We have developed an externally validated model to predict survival without tracheostomy and non-invasive ventilation for more than 23 h per day in European patients with ALS. This model could be applied to individualised patient management, counselling, and future trial design, but to maximise the benefit and prevent harm it is intended to be used by medical doctors only., Funding: Netherlands ALS Foundation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
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- 2018
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200. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.
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Nicolas A, Kenna KP, Renton AE, Ticozzi N, Faghri F, Chia R, Dominov JA, Kenna BJ, Nalls MA, Keagle P, Rivera AM, van Rheenen W, Murphy NA, van Vugt JJFA, Geiger JT, Van der Spek RA, Pliner HA, Shankaracharya, Smith BN, Marangi G, Topp SD, Abramzon Y, Gkazi AS, Eicher JD, Kenna A, Mora G, Calvo A, Mazzini L, Riva N, Mandrioli J, Caponnetto C, Battistini S, Volanti P, La Bella V, Conforti FL, Borghero G, Messina S, Simone IL, Trojsi F, Salvi F, Logullo FO, D'Alfonso S, Corrado L, Capasso M, Ferrucci L, Moreno CAM, Kamalakaran S, Goldstein DB, Gitler AD, Harris T, Myers RM, Phatnani H, Musunuri RL, Evani US, Abhyankar A, Zody MC, Kaye J, Finkbeiner S, Wyman SK, LeNail A, Lima L, Fraenkel E, Svendsen CN, Thompson LM, Van Eyk JE, Berry JD, Miller TM, Kolb SJ, Cudkowicz M, Baxi E, Benatar M, Taylor JP, Rampersaud E, Wu G, Wuu J, Lauria G, Verde F, Fogh I, Tiloca C, Comi GP, Sorarù G, Cereda C, Corcia P, Laaksovirta H, Myllykangas L, Jansson L, Valori M, Ealing J, Hamdalla H, Rollinson S, Pickering-Brown S, Orrell RW, Sidle KC, Malaspina A, Hardy J, Singleton AB, Johnson JO, Arepalli S, Sapp PC, McKenna-Yasek D, Polak M, Asress S, Al-Sarraj S, King A, Troakes C, Vance C, de Belleroche J, Baas F, Ten Asbroek ALMA, Muñoz-Blanco JL, Hernandez DG, Ding J, Gibbs JR, Scholz SW, Floeter MK, Campbell RH, Landi F, Bowser R, Pulst SM, Ravits JM, MacGowan DJL, Kirby J, Pioro EP, Pamphlett R, Broach J, Gerhard G, Dunckley TL, Brady CB, Kowall NW, Troncoso JC, Le Ber I, Mouzat K, Lumbroso S, Heiman-Patterson TD, Kamel F, Van Den Bosch L, Baloh RH, Strom TM, Meitinger T, Shatunov A, Van Eijk KR, de Carvalho M, Kooyman M, Middelkoop B, Moisse M, McLaughlin RL, Van Es MA, Weber M, Boylan KB, Van Blitterswijk M, Rademakers R, Morrison KE, Basak AN, Mora JS, Drory VE, Shaw PJ, Turner MR, Talbot K, Hardiman O, Williams KL, Fifita JA, Nicholson GA, Blair IP, Rouleau GA, Esteban-Pérez J, García-Redondo A, Al-Chalabi A, Rogaeva E, Zinman L, Ostrow LW, Maragakis NJ, Rothstein JD, Simmons Z, Cooper-Knock J, Brice A, Goutman SA, Feldman EL, Gibson SB, Taroni F, Ratti A, Gellera C, Van Damme P, Robberecht W, Fratta P, Sabatelli M, Lunetta C, Ludolph AC, Andersen PM, Weishaupt JH, Camu W, Trojanowski JQ, Van Deerlin VM, Brown RH Jr, van den Berg LH, Veldink JH, Harms MB, Glass JD, Stone DJ, Tienari P, Silani V, Chiò A, Shaw CE, Traynor BJ, and Landers JE
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- Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Amyotrophic Lateral Sclerosis epidemiology, Cohort Studies, Female, Humans, Male, Middle Aged, Young Adult, Amyotrophic Lateral Sclerosis diagnosis, Amyotrophic Lateral Sclerosis genetics, Genome-Wide Association Study methods, Kinesins genetics, Loss of Function Mutation genetics
- Abstract
To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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