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1. Mutations in the tail and rod domains of the neurofilament heavy‐chain gene increase the risk of ALS

Author

Heather Marriott, Thomas P. Spargo, Ahmad Al Khleifat, Peter M Andersen, Nazli A. Başak, Johnathan Cooper‐Knock, Philippe Corcia, Philippe Couratier, Mamede deCarvalho, Vivian Drory, Marc Gotkine, John E. Landers, Russell McLaughlin, Jesús S. Mora Pardina, Karen E. Morrison, Susana Pinto, Christopher E. Shaw, Pamela J. Shaw, Vincenzo Silani, Nicola Ticozzi, Philip vanDamme, Leonard H. van denBerg, Patrick Vourc'h, Markus Weber, Jan H. Veldink, Project MinE ALS Sequencing Consortium, Richard J. Dobson, Patrick Schwab, Ammar Al‐Chalabi, and Alfredo Iacoangeli

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Objective Neurofilament heavy‐chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk. Methods Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta‐analyses of published case–control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole‐genome sequencing data. Results Fixed‐effects meta‐analysis found that rare (MAF

Published
2024
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2. Caffeine consumption outcomes on amyotrophic lateral sclerosis disease progression and cognition

Author

Vincent Huin, David Blum, Violette Delforge, Emeline Cailliau, Sofia Djeziri, Kathy Dujardin, Alexandre Genet, Romain Viard, Shahram Attarian, Gaelle Bruneteau, Julien Cassereau, Steeve Genestet, Anne-Laure Kaminsky, Marie-Hélène Soriani, Mathilde Lefilliatre, Philippe Couratier, Sophie Pittion-Vouyovitch, Florence Esselin, Elisa De La Cruz, Nathalie Guy, Ivan Kolev, Philippe Corcia, Pascal Cintas, Claude Desnuelle, Luc Buée, Véronique Danel-Brunaud, David Devos, and Anne-Sophie Rolland

Subjects
Amyotrophic lateral sclerosis, Caffeine, Single nucleotide polymorphism, Cognition, Nutrition, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.

Published
2024
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3. Author Correction: Integrative genetic analysis illuminates ALS heritability and identifies risk genes

Author

Salim Megat, Natalia Mora, Jason Sanogo, Olga Roman, Alberto Catanese, Najwa Ouali Alami, Axel Freischmidt, Xhuljana Mingaj, Hortense De Calbiac, François Muratet, Sylvie Dirrig-Grosch, Stéphane Dieterle, Nick Van Bakel, Kathrin Müller, Kirsten Sieverding, Jochen Weishaupt, Peter Munch Andersen, Markus Weber, Christoph Neuwirth, Markus Margelisch, Andreas Sommacal, Kristel R. Van Eijk, Jan H. Veldink, Project Mine Als Sequencing Consortium, Géraldine Lautrette, Philippe Couratier, Agnès Camuzat, Isabelle Le Ber, Maurizio Grassano, Adriano Chio, Tobias Boeckers, Albert C. Ludolph, Francesco Roselli, Deniz Yilmazer-Hanke, Stéphanie Millecamps, Edor Kabashi, Erik Storkebaum, Chantal Sellier, and Luc Dupuis

Subjects
Science
Published
2023
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4. Integrative genetic analysis illuminates ALS heritability and identifies risk genes

Author

Salim Megat, Natalia Mora, Jason Sanogo, Olga Roman, Alberto Catanese, Najwa Ouali Alami, Axel Freischmidt, Xhuljana Mingaj, Hortense De Calbiac, François Muratet, Sylvie Dirrig-Grosch, Stéphane Dieterle, Nick Van Bakel, Kathrin Müller, Kirsten Sieverding, Jochen Weishaupt, Peter Munch Andersen, Markus Weber, Christoph Neuwirth, Markus Margelisch, Andreas Sommacal, Kristel R. Van Eijk, Jan H. Veldink, Project Mine Als Sequencing Consortium, Géraldine Lautrette, Philippe Couratier, Agnès Camuzat, Isabelle Le Ber, Maurizio Grassano, Adriano Chio, Tobias Boeckers, Albert C. Ludolph, Francesco Roselli, Deniz Yilmazer-Hanke, Stéphanie Millecamps, Edor Kabashi, Erik Storkebaum, Chantal Sellier, and Luc Dupuis

Subjects
Science
Abstract

Abstract Amyotrophic lateral sclerosis (ALS) has substantial heritability, in part shared with fronto-temporal dementia (FTD). We show that ALS heritability is enriched in splicing variants and in binding sites of 6 RNA-binding proteins including TDP-43 and FUS. A transcriptome wide association study (TWAS) identified 6 loci associated with ALS, including in NUP50 encoding for the nucleopore basket protein NUP50. Independently, rare variants in NUP50 were associated with ALS risk (P = 3.71.10−03; odds ratio = 3.29; 95%CI, 1.37 to 7.87) in a cohort of 9,390 ALS/FTD patients and 4,594 controls. Cells from one patient carrying a NUP50 frameshift mutation displayed a decreased level of NUP50. Loss of NUP50 leads to death of cultured neurons, and motor defects in Drosophila and zebrafish. Thus, our study identifies alterations in splicing in neurons as critical in ALS and provides genetic evidence linking nuclear pore defects to ALS.

Published
2023
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5. Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival

Author

Brett N. Adey, Johnathan Cooper-Knock, Ahmad Al Khleifat, Isabella Fogh, Philip van Damme, Philippe Corcia, Philippe Couratier, Orla Hardiman, Russell McLaughlin, Marc Gotkine, Vivian Drory, Vincenzo Silani, Nicola Ticozzi, Jan H. Veldink, Leonard H. van den Berg, Mamede de Carvalho, Susana Pinto, Jesus S. Mora Pardina, Mónica Povedano Panades, Peter M. Andersen, Markus Weber, Nazli A. Başak, Christopher E. Shaw, Pamela J. Shaw, Karen E. Morrison, John E. Landers, Jonathan D. Glass, Patrick Vourc’h, Richard J. B. Dobson, Gerome Breen, Ammar Al-Chalabi, Ashley R. Jones, and Alfredo Iacoangeli

Subjects
ALS (Amyotrophic lateral sclerosis), neurodegeneration, differential expression analysis (DEA), survival analysis, caveolin, Cav, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts.Methods: Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype.Results: We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days.Discussion: These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion.

Published
2023
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6. Tauroursodeoxycholic acid in patients with amyotrophic lateral sclerosis: The TUDCA-ALS trial protocol

Author

Alberto Albanese, Albert Christian Ludolph, Christopher J. McDermott, Philippe Corcia, Philip Van Damme, Leonard H. Van den Berg, Orla Hardiman, Gilberto Rinaldi, Nicola Vanacore, Brian Dickie, TUDCA-ALS Study Group, Paolo Tornese, Antoniangela Cocco, Maria Lo Giudice, Michela Matteoli, Eliana Lauranzano, Maria Luisa Malosio, Chiara Adriana Elia, Flavia Lombardo, Flavia Mayer, Maria Puopolo, Stefania Spila Alegiani, Adriano Chiò, Umberto Manera, Cristina Moglia, Andrea Calvo, Paolina Salamone, Giuseppe Fuda, Carlo Colosimo, Cristina Spera, Prabha Cristina Ranchicchio, Giuseppe Stipa, Domenico Frondizi, Christian Lunetta, Valeria Sansone, Claudia Tarlarini, Francesca Gerardi, Vincenzo Silani, Alberto Doretti, Eleonora Colombo, Gianluca Demirtzidis, Gioacchino Tedeschi, Francesca Trojsi, Carla Passaniti, Stefania Ballestrero, Johannes Dorst, Ulrike Weiland, Andrea Fromm, Maximilian Wiesenfarth, Katharina Kandler, Simon Witzel, Markus Otto, Joachim Schuster, Thomas Meyer, André Maier, Dagmar Kettemann, Susanne Petri, Lars Müschen, Camilla Wohnrade, Anastasia Sarikidi, Alma Osmanovic, Julian Grosskreutz, Annekathrin Rödiger, Robert Steinbach, Benjamin Ilse, Uta Smesny, Robert Untucht, René Günther, Maximilian Vidovic, Pamela Shaw, Alexis Collins, Helen Wollff, Theresa Walsh, Lee Tuddenham, Mbombe Kazoka, David White, Stacy Young, Benjamin Thompson, Daniel Madarshahian, Suresh K. Chhetri, Amina Chaouch, Carolyn A. Young, Heike Arndt, Oliver C Hanemann, Thomas Lambert, Stephane Beltran, Philippe Couratier, Florence Esselin, William Camu, Elisa De, La Cruz, Gwendal Lemasson, Pegah Masrori, Sinead Maguire, Liz Fogarty, Toyosi Atoyebi, and Niamh Ní Obáin

Subjects
amyotrophic lateral sclerosis, therapy, clinical trial, phase III, bile acids, Neurology. Diseases of the nervous system, RC346-429
Abstract

BackgroundAmyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative rare disease that affects motor neurons in the brain, brainstem, and spinal cord, resulting in progressive weakness and atrophy of voluntary skeletal muscles. Although much has been achieved in understanding the disease pathogenesis, treatment options are limited, and in Europe, riluzole is the only approved drug. Recently, some other drugs showed minor effects.MethodsThe TUDCA-ALS trial is a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The study aims to enroll 320 patients in 25 centers across seven countries in Europe. Enrolled patients are randomized to one of two treatment arms: TUDCA or identical placebo by oral route. The study measures disease progression during the treatment period and compares it to natural progression during a no-treatment run-in phase. Clinical data and specific biomarkers are measured during the trial. The study is coordinated by a consortium composed of leading European ALS centers.ConclusionThis trial is aimed to determine whether TUDCA has a disease-modifying activity in ALS. Demonstration of TUDCA efficacy, combined with the validation of new biomarkers, could advance ALS patient care.Clinical trial registrationClinicalTrials.gov, identifier: NCT03800524.

Published
2022
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7. The French national protocol for Kennedy’s disease (SBMA): consensus diagnostic and management recommendations

Author

Pierre-François Pradat, Emilien Bernard, Philippe Corcia, Philippe Couratier, Christel Jublanc, Giorgia Querin, Capucine Morélot Panzini, François Salachas, Christophe Vial, Karim Wahbi, Peter Bede, Claude Desnuelle, and on behalf of the French Kennedy’s Disease Writing Group

Subjects
Kennedy disease, Spinal and bulbar muscular atrophy, Guidelines, Polyglutamine, Androgen receptor, Androgen insensitivity, Medicine
Abstract

Abstract Background Kennedy’s disease (KD), also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, X-linked recessive neuromuscular disease caused by CAG expansions in exon 1 of the androgen receptor gene (AR). The objective of the French national diagnostic and management protocol is to provide evidence-based best practice recommendations and outline an optimised care pathway for patients with KD, based on a systematic literature review and consensus multidisciplinary observations. Results The initial evaluation, confirmation of the diagnosis, and management should ideally take place in a tertiary referral centre for motor neuron diseases, and involve an experienced multidisciplinary team of neurologists, endocrinologists, cardiologists and allied healthcare professionals. The diagnosis should be suspected in an adult male presenting with slowly progressive lower motor neuron symptoms, typically affecting the lower limbs at onset. Bulbar involvement (dysarthria and dysphagia) is often a later manifestation of the disease. Gynecomastia is not a constant feature, but is suggestive of a suspected diagnosis, which is further supported by electromyography showing diffuse motor neuron involvement often with asymptomatic sensory changes. A suspected diagnosis is confirmed by genetic testing. The multidisciplinary assessment should ascertain extra-neurological involvement such as cardiac repolarisation abnormalities (Brugada syndrome), signs of androgen resistance, genitourinary abnormalities, endocrine and metabolic changes (glucose intolerance, hyperlipidemia). In the absence of effective disease modifying therapies, the mainstay of management is symptomatic support using rehabilitation strategies (physiotherapy and speech therapy). Nutritional evaluation by an expert dietician is essential, and enteral nutrition (gastrostomy) may be required. Respiratory management centres on the detection and treatment of bronchial obstructions, as well as screening for aspiration pneumonia (chest physiotherapy, drainage, positioning, breath stacking, mechanical insufflation-exsufflation, cough assist machnie, antibiotics). Non-invasive mechanical ventilation is seldom needed. Symptomatic pharmaceutical therapy includes pain management, endocrine and metabolic interventions. There is no evidence for androgen substitution therapy. Conclusion The French national Kennedy’s disease protocol provides management recommendations for patients with KD. In a low-incidence condition, sharing and integrating regional expertise, multidisciplinary experience and defining consensus best-practice recommendations is particularly important. Well-coordinated collaborative efforts will ultimately pave the way to the development of evidence-based international guidelines.

Published
2020
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8. Frontotemporal Pathology in Motor Neuron Disease Phenotypes: Insights From Neuroimaging

Author

Mary Clare McKenna, Philippe Corcia, Philippe Couratier, We Fong Siah, Pierre-Francois Pradat, and Peter Bede

Subjects
ALS, MND, PLS, MRI, PET, SMA, Neurology. Diseases of the nervous system, RC346-429
Abstract

Frontotemporal involvement has been extensively investigated in amyotrophic lateral sclerosis (ALS) but remains relatively poorly characterized in other motor neuron disease (MND) phenotypes such as primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), spinal muscular atrophy (SMA), spinal bulbar muscular atrophy (SBMA), post poliomyelitis syndrome (PPS), and hereditary spastic paraplegia (HSP). This review focuses on insights from structural, metabolic, and functional neuroimaging studies that have advanced our understanding of extra-motor disease burden in these phenotypes. The imaging literature is limited in the majority of these conditions and frontotemporal involvement has been primarily evaluated by neuropsychology and post mortem studies. Existing imaging studies reveal that frontotemporal degeneration can be readily detected in ALS and PLS, varying degree of frontotemporal pathology may be captured in PMA, SBMA, and HSP, SMA exhibits cerebral involvement without regional predilection, and there is limited evidence for cerebral changes in PPS. Our review confirms the heterogeneity extra-motor pathology across the spectrum of MNDs and highlights the role of neuroimaging in characterizing anatomical patterns of disease burden in vivo. Despite the contribution of neuroimaging to MND research, sample size limitations, inclusion bias, attrition rates in longitudinal studies, and methodological constraints need to be carefully considered. Frontotemporal involvement is a quintessential clinical facet of MND which has important implications for screening practices, individualized management strategies, participation in clinical trials, caregiver burden, and resource allocation. The academic relevance of imaging frontotemporal pathology in MND spans from the identification of genetic variants, through the ascertainment of presymptomatic changes to the design of future epidemiology studies.

Published
2021
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10. Current view and perspectives in amyotrophic lateral sclerosis

Author

Stéphane Mathis, Philippe Couratier, Adrien Julian, Philippe Corcia, and Gwendal Le Masson

Subjects
amyotrophic lateral sclerosis, Charcot, biomarkers, research, motor neuron, neurodegeneration, Neurology. Diseases of the nervous system, RC346-429
Abstract

Amyotrophic lateral sclerosis (ALS), identified as a distinct clinical entity by Charcot since the end of the nineteenth century, is a devastating and fatal neurodegenerative disorder that affects motor neurons in the brain, brainstem and spinal cord. Survival of patients with ALS is associated with several factors such as clinical phenotype, age at onset, gender, early presence of respiratory failure, weight loss and treatment with Riluzole (the only disease-modifying drug approved for this disease). Nowadays, there is still no curative treatment for ALS: palliative care and symptomatic treatment are therefore essential components in the management of these patients. Nevertheless, the scientific knowledge in the field of ALS motor neuron degeneration is growing, with the prospect of new treatments. Based on this physiopathological knowledge, several new therapeutic targets are being studied, involving various mechanisms such as excitotoxicity, neuroinflammation, mitochondrial dysfunction, oxidative stress, RNA metabolism and other attractive concepts. Moreover, it is also important to identify reliable biomarkers that will be essential components for future therapeutic development and study design in ALS. In this review, we present the main recent advances and promising therapeutics and biomarkers in the field of ALS.

Published
2017
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11. Structural, Microstructural, and Metabolic Alterations in Primary Progressive Aphasia Variants

Author

Alexandre Routier, Marie-Odile Habert, Anne Bertrand, Aurélie Kas, Martina Sundqvist, Justine Mertz, Pierre-Maxime David, Hugo Bertin, Serge Belliard, Florence Pasquier, Karim Bennys, Olivier Martinaud, Frédérique Etcharry-Bouyx, Olivier Moreaud, Olivier Godefroy, Jérémie Pariente, Michèle Puel, Philippe Couratier, Claire Boutoleau-Bretonnière, Bernard Laurent, Raphaëlla Migliaccio, Bruno Dubois, Olivier Colliot, and Marc Teichmann

Subjects
primary progressive aphasias, cortical thickness, cortical metabolism, tracts, MRI, PET, Neurology. Diseases of the nervous system, RC346-429
Abstract

Neuroimaging studies have described the brain alterations in primary progressive aphasia (PPA) variants (semantic, logopenic, nonfluent/agrammatic). However, few studies combined T1, FDG-PET, and diffusion MRI techniques to study atrophy, hypometabolism, and tract alterations across the three PPA main variants. We therefore explored a large early-stage cohort of semantic, logopenic and nonfluent/agrammatic variants (N = 86) and of 23 matched healthy controls with anatomical MRI (cortical thickness), FDG PET (metabolism) and diffusion MRI (white matter tracts analyses), aiming at identifying cortical and sub-cortical brain alterations, and confronting these alterations across imaging modalities and aphasia variants. In the semantic variant, there was cortical thinning and hypometabolism in anterior temporal cortices, with left-hemisphere predominance, extending toward posterior temporal regions, and affecting tracts projecting to the anterior temporal lobes (inferior longitudinal fasciculus, uncinate fasciculus) and tracts projecting to or running nearby posterior temporal cortices: (superior longitudinal fasciculus, inferior frontal-occipital fasciculus). In the logopenic variant metabolic alterations were more extensive than atrophy affecting mainly the left temporal-parietal junction and extending toward more anterior temporal cortices. Metabolic and tract data were coherent given the alterations of the left superior and inferior longitudinal fasciculus and the left inferior frontal-occipital fasciculus. In the nonfluent/agrammatic variant cortical thinning and hypometabolism were located in the left frontal cortex but Broca's area was only affected on metabolic measures. Metabolic and tract alterations were coherent as reflected by damage to the left uncinate fasciculus connecting with Broca's area. Our findings provide a full-blown statistically robust picture of brain alterations in early-stage variants of primary progressive aphasia which has implications for diagnosis, classification and future therapeutic strategies. They demonstrate that in logopenic and semantic variants patterns of brain damage display a non-negligible overlap in temporal regions whereas they are substantially distinct in the nonfluent/agrammatic variant (frontal regions). These results also indicate that frontal networks (combinatorial syntax/phonology) and temporal networks (lexical/semantic representations) constitute distinct anatomo-functional entities with differential vulnerability to degenerative processes in aphasia variants. Finally, the identification of the specific damage patterns could open an avenue for trans-cranial stimulation approaches by indicating the appropriate target-entry into the damaged language system.

Published
2018
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12. Referral bias in ALS epidemiological studies.

Author

Giancarlo Logroscino, Benoit Marin, Marco Piccininni, Simona Arcuti, Adriano Chiò, Orla Hardiman, James Rooney, Stefano Zoccolella, Philippe Couratier, Pierre-Marie Preux, Ettore Beghi, and for EURALS

Subjects
Medicine, Science
Abstract

Despite concerns about the representativeness of patients from ALS tertiary centers as compared to the ALS general population, the extent of referral bias in clinical studies remains largely unknown. Using data from EURALS consortium we aimed to assess nature, extent and impact of referral bias.Four European ALS population-based registries located in Ireland, Piedmont, Puglia, Italy, and Limousin, France, covering 50 million person-years, participated. Demographic and clinic characteristics of ALS patients diagnosed in tertiary referral centers were contrasted with the whole ALS populations enrolled in registries in the same geographical areas.Patients referred to ALS centers were younger (with difference ranging from 1.1 years to 2.4 years), less likely to present a bulbar onset, with a higher proportion of familial antecedents and a longer survival (ranging from 11% to 15%) when compared to the entire ALS population in the same geographic area.A trend for referral bias is present in cohorts drawn from ALS referral centers. The magnitude of the possible referral bias in a particular tertiary center can be estimated through a comparison with ALS patients drawn from registry in the same geographic area. Studies based on clinical cohorts should be cautiously interpreted. The presence of a registry in the same area may improve the complete ascertainment in the referral center.

Published
2018
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13. Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype

Author

Johnathan Cooper-Knock, Henry Robins, Isabell Niedermoser, Matthew Wyles, Paul R. Heath, Adrian Higginbottom, Theresa Walsh, Mbombe Kazoka, Project MinE ALS Sequencing Consortium, Paul G. Ince, Guillaume M. Hautbergue, Christopher J. McDermott, Janine Kirby, Pamela J. Shaw, Ahmad Al Kheifat, Ammar Al-Chalabi, Nazli Basak, Ian Blair, Annelot Dekker, Orla Hardiman, Winston Hide, Alfredo Iacoangeli, Kevin Kenna, John Landers, Russel McLaughlin, Jonathan Mill, Bas Middelkoop, Mattieu Moisse, Jesus Mora Pardina, Karen Morrison, Stephen Newhouse, Sara Pulit, Aleksey Shatunov, Chris Shaw, William Sproviero, Gijs Tazelaar, Philip van Damme, Leonard van den Berg, Rick van der Spek, Kristelvan Eijk, Michael van Es, Wouter van Rheenen, Joke van Vugt, Jan Veldink, Maarten Kooyman, Jonathan Glass, Wim Robberecht, Marc Gotkine, Vivian Drory, Matthew Kiernan, Miguel Mitne Neto, Mayana Ztaz, Philippe Couratier, Philippe Corcia, Vincenzo Silani, Adriano Chio, Mamede de Carvalho, Susana Pinto, Alberto Garcia Redondo, Peter Andersen, Markus Weber, and Nicola Ticozzi

Subjects
amyotrophic lateral sclerosis, RNA binding proteins, oligogenic inheritance, C9ORF72, DNA sequencing, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025). Our data are consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development.

Published
2017
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14. Contributors

Author

Alexiou, Athanasios, primary, Amenta, Francesco, additional, Amoroso, Nicola, additional, Andrews, Jessica L., additional, Arba, Francesco, additional, Armato, Ubaldo, additional, Ashraf, Ghulam Md, additional, Attardo, Lapo, additional, Avelino-Silva, Thiago Junqueira, additional, Ayres, Annelise, additional, Bagetta, Giacinto, additional, Balietti, Marta, additional, Battineni, Gopi, additional, Beheshti, Siamak, additional, Belbasis, Lazaros, additional, Bellou, Vanesa, additional, Bergantin, Leandro Bueno, additional, Berríos, Waleska, additional, Boccardi, Virginia, additional, Bosco, Andrea, additional, Briggs, Robert, additional, Burtscher, Johannes, additional, Burtscher, Martin, additional, Caffò, Alessandro O., additional, Cajas-Salazar, Nohelia, additional, Callisaya, Michele L., additional, Caricati-Neto, Afonso, additional, Carlesi, Cecilia, additional, Castillo-Ordoñez, Willian Orlando, additional, Chan, Victor T.T., additional, Chatzichronis, Stylianos, additional, Cheung, Carol Y., additional, Chiarini, Anna M., additional, Cipollini, Virginia, additional, Cipriani, Gabriele, additional, Claeysen, Sylvie, additional, Claffey, Paul, additional, Clarnette, Roger, additional, Corasaniti, Maria Tiziana, additional, Cornelis, Elise, additional, Dal Prà, Ilaria, additional, Darvesh, Sultan, additional, DeBay, Drew R., additional, Del Dotto, Paolo, additional, De Reuck, Jacques, additional, De Vriendt, Patricia, additional, Dharmadasa, Thanuja, additional, Dovey, Kathryn, additional, Downey, H. Fred, additional, Dyer, Adam H., additional, Eccher, Claudio, additional, Endres, Kristina, additional, Evangelou, Evangelos, additional, Fernandez, Francesca, additional, Fong Yan, Alycia, additional, Frith, Emily, additional, Garcez, Flavia Barreto, additional, Giannoni, Patrizia, additional, Giubilei, Franco, additional, Glazachev, Oleg S., additional, Glynn-Servedio, B.E., additional, Golimstok, Angel, additional, Gorus, Ellen, additional, Gottesman, Rebecca F., additional, Hatashita, Shizuo, additional, Holle, Bernhard, additional, Housseini, Mahboobeh, additional, Huynh, William, additional, Ienco, Elena Caldarazzo, additional, Ismeurt, Caroline, additional, Jayakody, Oshadi, additional, Kamalraj, Pabiththa, additional, Wolf-Ostermann, Karin, additional, Kawaguchi, Kazunori, additional, Kennelly, Sean P., additional, Kiernan, Matthew C., additional, King, Anna E., additional, Kitaguchi, Nobuya, additional, Kito, Shinsuke, additional, Laporte Uribe, Franziska, additional, Liu, Yue, additional, Lopez, Antonella, additional, Loprinzi, Paul D., additional, Low, Lee-Fay, additional, Mallet, Robert T., additional, Manukhina, Eugenia B., additional, Marucci, Gabriella, additional, Matias-Guiu, Jordi A., additional, Matthew Wai Kin, Wong, additional, Mecocci, Patrizia, additional, Molloy, D. William, additional, Monteleone, Domenico, additional, Morrone, Luigi Antonio, additional, Moruzzi, Michele, additional, Müller, Thomas, additional, Nady, Braidy, additional, Nunomura, Akihiko, additional, Nuti, Angelo, additional, O'Caoimh, Rónán, additional, O'Halloran, Paul, additional, Padovani, Marina, additional, Pallotta, Graziano, additional, Paolacci, Lucia, additional, Parker, Helen, additional, Perminder Singh, Sachdev, additional, Philippe, Couratier, additional, Poljak, Anne, additional, Raglio, Alfredo, additional, Rainero, Innocenzo, additional, Regan, Bridget, additional, Reid, Larry D., additional, Reinhardt, Sven, additional, René Thyrian, Jochen, additional, Rinnoci, Valentina, additional, Río-Sancho, Sergio del, additional, Rombolà, Laura, additional, Rozenfeld Olchik, Maira, additional, Rubino, Elisa, additional, Sakai, Kazuyoshi, additional, Sakurada, Tsukasa, additional, Sakurada, Shinobu, additional, Savundranayagam, Marie Y., additional, Scorza, Fúlvio Alexandre, additional, Scuteri, Damiana, additional, Serebrovskaya, Tatiana V., additional, Shigeta, Masahiro, additional, Shinagawa, Shunichiro, additional, Spano, Giuseppina, additional, Stuart, Kimberley E., additional, Tagai, Kenji, additional, Tamaoki, Toshio, additional, Taylor, Dylan Z., additional, Traini, Enea, additional, Troili, Fernanda, additional, Vacca, Alessandro, additional, Vickers, James C., additional, Walf, Alicia A., additional, Walker, Keenan A., additional, Wells, Yvonne, additional, Woltjer, Randall J., additional, and Wood, Paul L., additional

Published
2020
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16. COURAGE-ALS: a randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success

Author

Jeremy M. Shefner, Ammar Al-Chalabi, Jinsy A. Andrews, Adriano Chio, Mamede De Carvalho, Bettina M. Cockroft, Philippe Corcia, Philippe Couratier, Merit E. Cudkowicz, Angela Genge, Orla Hardiman, Terry Heiman-Patterson, Robert D. Henderson, Caroline Ingre, Carlayne E. Jackson, Wendy Johnston, Noah Lechtzin, Albert Ludolph, Nicholas J. Maragakis, Timothy M. Miller, Jesus S. Mora Pardina, Susanne Petri, Zachary Simmons, Leonard H. Van Den Berg, Lorne Zinman, Stuart Kupfer, Fady I. Malik, Lisa Meng, Tyrell J. Simkins, Jenny Wei, Andrew A. Wolff, and Stacy A. Rudnicki

Subjects
Neurology, Neurology (clinical)
Published
2023
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17. Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival

Author

Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Adey, Brett N.; Cooper-Knock, Johnathan; Al Khleifat, Ahmad; Fogh, Isabella; van Damme, Philip; Corcia, Philippe; Couratier, Philippe; Hardiman, Orla; McLaughlin, Russell; Gotkine, Marc; Drory, Vivian; Silani, Vincenzo; Ticozzi, Nicola; Veldink, Jan H.; van den Berg, Leonard H.; de Carvalho, Mamede; Pinto, Susana; Mora Pardina, Jesus S.; Povedano Panades, Mónica; Andersen, Peter M.; Weber, Markus; Shaw, Christopher E.; Shaw, Pamela J.; Morrison, Karen E.; Landers, John E.; Glass, Jonathan D.; Vourc’h, Patrick; Dobson, Richard J. B.; Breen, Gerome; Al-Chalabi, Ammar; Jones, Ashley R.; Iacoangeli, Alfredo, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Adey, Brett N.; Cooper-Knock, Johnathan; Al Khleifat, Ahmad; Fogh, Isabella; van Damme, Philip; Corcia, Philippe; Couratier, Philippe; Hardiman, Orla; McLaughlin, Russell; Gotkine, Marc; Drory, Vivian; Silani, Vincenzo; Ticozzi, Nicola; Veldink, Jan H.; van den Berg, Leonard H.; de Carvalho, Mamede; Pinto, Susana; Mora Pardina, Jesus S.; Povedano Panades, Mónica; Andersen, Peter M.; Weber, Markus; Shaw, Christopher E.; Shaw, Pamela J.; Morrison, Karen E.; Landers, John E.; Glass, Jonathan D.; Vourc’h, Patrick; Dobson, Richard J. B.; Breen, Gerome; Al-Chalabi, Ammar; Jones, Ashley R.; Iacoangeli, Alfredo, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine

Abstract

Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Methods: using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype. Results: we report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days. Discussion: these results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion., We would like to acknowledge funding from the following funders: UK Research and Innovation; Medical Research Council; South London and Maudsley NHS Foundation Trust; MND Scotland; Motor Neurone Disease Association; National Institute for Health Research; Spastic Paraplegia Foundation; Rosetrees Trust; Darby Rimmer MND Foundation. Funding for open access charge: UKRI. BA acknowledges funding from an NIHR pre-doctoral fellowship (NIHR301067). AI is funded by the Motor Neurone Disease Association and South London and Maudsley NHS Foundation Trust. JC-K is supported by a Wellcome Trust fellowship (216596/Z/19/Z). AAK is funded by ALS Association Milton Safenowitz Research Fellowship (grant number 22-PDF-609. DOI: 10.52546/pc.gr.150909.), The Motor Neurone Disease Association (MNDA) Fellowship (AAK/Oct21/975-799), The Darby Rimmer Foundation, and The NIHR Maudsley Biomedical Research Centre. This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND: http://www.neurodegenerationresearch.eu/ [United Kingdom, Medical Research Council MR/L501529/1 to AA-C, principal investigator (PI) and MR/R024804/1 to AA-C, PI; Economic and Social Research Council ES/L008238/1 to AA-C (co-PI)] and through the Motor Neurone Disease Association. This study represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The work leading up to this publication was funded by the European Community’s Horizon 2020 Programme (H2020-PHC-2014-two-stage; grant 633413). We acknowledge use of the research computing facility at King’s College London, Rosalind ( https://rosalind.kcl.ac.uk ), which is delivered in partnership with the National Institute for Health Research (NIHR) Biomedical Research Centres at South London and Maudsley and Guy’s and St.

Published
2023

19. Genetic variability in sporadic amyotrophic lateral sclerosis

Author

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

Subjects
Neurology (clinical)
Abstract

With the advent of gene therapies for amyotrophic lateral sclerosis, there is a surge in gene testing for ALS. 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 with genetic variants with large and small effect sizes. Guidelines for 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 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 (OR 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. 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.

Published
2023
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20. Consensus d'experts sur les échelles et critères utilisés en pratique pour le diagnostic et le suivi de la sclérose latérale amyotrophique en France

Author

Annie Verschueren, Emilien Bernard, Julien Cassereau, Steeve Genestet, Philippe Couratier, Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de recours et de compétence pour la SLA, Hôpital Pierre Wertheimer - Bron, Neurologie, Centre de référence et de compétence SLA d'Angers, CHU Angers, Explorations fonctionnelles neurologiques, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre référent Sclérose Latérale Amyotrophique et autres maladies du motoneurone [CHU Limoges] (SLA CHU Limoges), CHU Limoges, Epidémiologie des Maladies Chroniques en zone tropicale (EpiMaCT), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-OmégaHealth (ΩHealth), and Université de Limoges (UNILIM)-Université de Limoges (UNILIM)

Subjects
Consensus, Neurology, [SDV]Life Sciences [q-bio], Sclérose latérale amyotrophique, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), Diagnostic
Abstract

International audience

Published
2023

22. Study of Ubiquitin Pathway Genes in a French Population with Amyotrophic Lateral Sclerosis: Focus on HECW1 Encoding the E3 Ligase NEDL1

Author

Shanez Haouari, Christian Robert Andres, Debora Lanznaster, Sylviane Marouillat, Céline Brulard, Audrey Dangoumau, Devina Ung, Charlotte Veyrat-Durebex, Frédéric Laumonnier, Hélène Blasco, Philippe Couratier, Philippe Corcia, and Patrick Vourc’h

Subjects
Inorganic Chemistry, amyotrophic lateral sclerosis, genetic, ALS, ubiquitin, HECW1, Organic Chemistry, General Medicine, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, Catalysis, Computer Science Applications
Abstract

The ubiquitin pathway, one of the main actors regulating cell signaling processes and cellular protein homeostasis, is directly involved in the pathophysiology of amyotrophic lateral sclerosis (ALS). We first analyzed, by a next-generation sequencing (NGS) strategy, a series of genes of the ubiquitin pathway in two cohorts of familial and sporadic ALS patients comprising 176 ALS patients. We identified several pathogenic variants in different genes of this ubiquitin pathway already described in ALS, such as FUS, CCNF and UBQLN2. Other variants of interest were discovered in new genes studied in this disease, in particular in the HECW1 gene. We have shown that the HECT E3 ligase called NEDL1, encoded by the HECW1 gene, is expressed in neurons, mainly in their somas. Its overexpression is associated with increased cell death in vitro and, very interestingly, with the cytoplasmic mislocalization of TDP-43, a major protein involved in ALS. These results give new support for the role of the ubiquitin pathway in ALS, and suggest further studies of the HECW1 gene and its protein NEDL1 in the pathophysiology of ALS.

Published
2023
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23. Primary progressive aphasias associated with C9orf72 expansions: Another side of the story

Author

idier Hannequin, Eino Solje, Sabrina Sayah, Emmanuel Gerardin, Marie Sarazin, Florence Pasquier, Marion Houot, Assi-Hervé Oya, Martine Vercelletto, Julien Lagarde, Marie Noguès-Lassiaille, Marie Chupin, Vincent Deramecourt, Sophie Auriacombe, Agnès Camuzat, Marc Teichmann, Jérémie Pariente, Sophie Ferrieux, Lucette Lacomblez, Mathieu Chastan, Jacques Monteil, Yaohua Chen, Marie-Paule Boncoeur, Lorenzo Cipriano, Anne Bissery, Simona Bottani, David Wallon, Christine Delmaire, Carole Roué-Jagot, Benjamin Le Toullec, Bernard-François Michel, Grégory Petyt, Olivier Martinaud, Philippe Couratier, Dario Saracino, Adeline Rollin-Sillaire, Daisy Rinaldi, Mira Didic, Serge Belliard, Amandine Géraudie, Géraldine Lautrette, Frédérique Etcharry-Bouyx, Xavier Delbeuck, Richard Levy, Frédéric Blanc, Mathieu Ceccaldi, Christel Thauvin-Robinet, Marie-Odile Habert, Eve Benchetrit, Maïté Formaglio, Alexis Brice, Isabelle Le Ber, Charles Duyckaerts, Véronique Golfier, Raffaella Migliaccio, Marie-Anne Mackowiak, Catherine Thomas-Antérion, Anne Bertrand, Olivier Colliot, François Sellal, Claire Boutoleau-Bretonnière, Anne M. Remes, Hugo Bertin, Aurélie Funkiewiez, and Stéphanie Bombois

Subjects
medicine.medical_specialty, C9orf72 Protein, Apraxias, Cognitive Neuroscience, Inferior frontal gyrus, Experimental and Cognitive Psychology, Frontotemporal lobar degeneration, respiratory system, Audiology, medicine.disease, Magnetic Resonance Imaging, Apraxia, Primary progressive aphasia, Aphasia, Primary Progressive, Neuropsychology and Physiological Psychology, Atrophy, C9orf72, medicine, Humans, Speech, Orbitofrontal cortex, Psychology, Language, Frontotemporal dementia
Abstract

C9orf72 repeat expansions are rarely associated with primary progressive aphasias (PPA). In-depth characterization of the linguistic deficits, and the underlying patterns of grey-matter atrophy in PPA associated with the C9orf72 expansions (PPA-C9orf72) are currently lacking. In this study, we comprehensively analyzed a unique series of 16 patients affected by PPA-C9orf72. Eleven patients were issued from two independent French and Finnish cohorts, and five were identified by means of literature review. Voxel-based morphometry (VBM) studies were performed on three of them. This study depicts the spectrum of C9orf72–related aphasic phenotypes, and illustrates their linguistic presentation. The non-fluent/agrammatic variant was the most frequent phenotype in our series (9/16 patients, 56%), with apraxia of speech being the main defining feature. Left frontal lobe atrophy was present in these subjects, peaking in inferior frontal gyrus. Three patients (19%) showed the semantic variant, with progression of atrophy in temporo-polar regions, later involving orbitofrontal cortex. Anterior temporal lobe dysfunction was also particularly relevant in two patients (12.5%) with mixed forms of PPA. Lastly, two patients (12.5%) had unclassifiable PPA with predominating word-finding difficulties. No PPA-C9orf72 patients in our series fulfilled the criteria of the logopenic variant. Importantly, this study underlines the role of C9orf72 mutation in the disruption of the most anterior parts of the language network, including prefrontal and temporo-polar areas. It provides guidelines for C9orf72 testing in PPA patients, with important clinical impact as gene-specific therapies are upcoming.

Published
2021
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24. Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial

Author

Michael Pulley, Mikko Kuoppamäki, Carolyn A Young, Jesus S. Mora Pardina, Kumaraswamy Sivakumar, Toni Sarapohja, Michael A. Elliott, Chafic Karam, Sandeep Rana, Orla Hardiman, Nathan P. Staff, Letizia Mazzini, Gabriele Mora, Thomas F. Meyer, Colleen O'Connell, Stéphanie Delstanche, Elham Bayat, Michael D. Weiss, Waqar Waheed, Nenad Mitrovic, Philippe Corcia, Marie-Hélène Soriani, Edward J. Kasarskis, Claudia Caponnetto, Dale J. Lange, Tuan Vu, Leo McCluskey, Berthold Schrank, Angela Genge, Matthew C. Kiernan, Valtteri V Aho, Manu Jokela, Philip Van Damme, Juan F. Vázquez Costa, Maurizio Inghilleri, Wolfgang Löscher, David Schultz, Tero Tapiola, Susanne Petri, Adriano Chiò, Gary L. Pattee, Julian Großkreutz, Ammar Al-Chalabi, Aziz Shaibani, Susan Mathers, Kevin J. Felice, Kimberly Goslin, James Caress, Matthias Boentert, Albert C. Ludolph, Aleksandar Radunovic, Robert D. Henderson, James Wymer, Todd Levine, Jakob Rath, Merrilee Needham, William Camu, Gaurav Guliani, Rune Johansson, Leonard H. van den Berg, Namita Goyal, Mark B. Bromberg, Bjorn Oskarsson, Annie Dionne, Eduardo Locatelli, Brent T. Harris, Suma Babu, Richard Bedlack, John Ravits, Jinsy A. Andrews, Philippe Couratier, Gabriele Siciliano, Hannu Laaksovirta, Kourosh Rezania, Lawrence Korngut, Eduardo Aguera Morales, Peter M Andersen, Eva Farrero Munoz, David Lacomis, Stephen N. Scelsa, Chris Garratt, Matthew Burford, Merit Cudkowicz, Nicholas J. Maragakis, Wendy Johnston, Martin M. Brown, Johannes Prudlo, Justin Y. Kwan, Dominic B. Fee, Senda Ajroud-Driss, Stephen A. Goutman, John Turnbull, Michael H. Rivner, Timothy M. Miller, Jan De Bleecker, Caroline Ingre, Luis Varona, Genevieve Matte, Daragh Heitzman, Robert Untucht, Lorne Zinman, Adam Quick, and Jonathan S. Katz

Subjects
education.field_of_study, medicine.medical_specialty, Supine position, business.industry, Amyotrophic Lateral Sclerosis, Population, Administration, Oral, Levosimendan, Placebo, Treatment Outcome, amyotrophic lateral sclerosis, levosimendan, randomised, double-blind, placebo-controlled trial, Double-Blind Method, Respiratory failure, Internal medicine, Clinical endpoint, Humans, Medicine, Respiratory function, Neurology (clinical), business, Adverse effect, education, Simendan, medicine.drug
Abstract

Summary Background There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function. Methods The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60–90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178 ) has also been completed, but will be reported separately. Findings Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5–51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4–48·1) weeks. Change from baseline in supine SVC at 12 weeks was –6·73% with levosimendan and –6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI –2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI –15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis. Interpretation Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation. Funding Orion Corporation.

Published
2021
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25. Oral edaravone demonstrated a favorable safety profile in patients with amyotrophic lateral sclerosis after 48 weeks of treatment

Author

Angela Genge, Gary L. Pattee, Gen Sobue, Masashi Aoki, Hiide Yoshino, Philippe Couratier, Christian Lunetta, Susanne Petri, Daniel Selness, Sachin Bidani, Manabu Hirai, Takeshi Sakata, Alejandro Salah, Stephen Apple, Art Wamil, Alexander Kalin, and Carlayne E. Jackson

Subjects
Cellular and Molecular Neuroscience, Physiology, Physiology (medical), Neurology (clinical)
Abstract

An intravenous (IV) formulation of edaravone has been shown to slow the rate of physical functional decline in amyotrophic lateral sclerosis (ALS). An oral suspension formulation of edaravone was recently approved by the United States Food and Drug Administration for use in patients with ALS. This study assessed the safety and tolerability of oral edaravone.This global, open-label, phase 3 study evaluated the long-term safety and tolerability of oral edaravone in adults with ALS who had a baseline forced vital capacity ≥70% of predicted and disease duration ≤3 y. The primary safety analysis was assessed at weeks 24 and 48. Patients received a 105-mg dose of oral edaravone in treatment cycles replicating the dosing of IV edaravone.The study enrolled 185 patients (64.3% male; mean age, 59.9 y; mean disease duration, 1.56 y). The most common treatment-emergent adverse events (TEAEs) at week 48 were fall (22.2%), muscular weakness (21.1%) and constipation (17.8%). Serious TEAEs were reported by 25.9% of patients; the most common were worsening ALS symptoms, dysphagia, dyspnea, and respiratory failure. Twelve TEAEs leading to death were reported. Forty-six (24.9%) patients reported TEAEs that were considered related to study drug; the most common were fatigue, dizziness, headache, and constipation. Sixteen (8.6%) patients discontinued study drug due to TEAEs. No serious TEAEs were related to study drug.This study indicated that oral edaravone was well tolerated during 48 wk of treatment, with no new safety concerns identified.

Published
2022

26. Large-scale Analyses of CAV1 and CAV2 Suggest Their Expression is Higher in Post-mortem ALS Brain Tissue and Affects Survival

Author

Brett N Adey, Johnathan Cooper-Knock, Ahmad Al Khleifat, Isabella Fogh, Philip van Damme, Philippe Corcia, Philippe Couratier, Orla Hardiman, Russell McLaughlin, Marc Gotkine, Vivian Drory, Vincenzo Silani, Nicola Ticozzi, Jan H. Veldink, Leonard H. van den Berg, Mamede de Carvalho, Susana Pinto, Jesus S. Mora Pardina, Monica Povedano, Peter M. Andersen, Markus Weber, Nazli A. Başak, Christopher E Shaw, Pamela J. Shaw, Karen E. Morrison, John E. Landers, Jonathan D. Glass, Patrick Vourc’h, Richard JB Dobson, Gerome Breen, Ammar Al-Chalabi, Ashley R Jones, and Alfredo Iacoangeli

Subjects
Neurologi, Settore MED/08 - Anatomia Patologica, ALS (Amyotrophic lateral sclerosis), AMYOTROPHIC-LATERAL-SCLEROSIS, survival analysis, Cellular and Molecular Neuroscience, enhancer variant, CAV1 and CAV2, CAVEOLIN-1, Science & Technology, neurodegeneration, Neurosciences, IDENTIFY, Cav, caveolin, differential expression analysis (DEA), Amyotrophic lateral sclerosis, Neurology, Marcadors genètics, Genetic markers, Settore MED/26 - Neurologia, Neurosciences & Neurology, Life Sciences & Biomedicine, ASSOCIATION ANALYSES, Esclerosi lateral amiotròfica, Neurovetenskaper
Abstract

Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts.Methods: Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype.Results: We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days.Discussion: These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion.

Published
2022
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27. Tauroursodeoxycholic acid in patients with amyotrophic lateral sclerosis: The TUDCA-ALS trial protocol

Author

Albanese Alberto, Ludolph, Albert Christian, McDermott, Christopher J, Corcia, Philippe, Van Damme, Philip, Van den Berg, Leonard H, Hardiman, Orla, Rinaldi, Gilberto, Vanacore, Nicola, Dickie, Brian, TUDCA-ALS Study Group, Paolo Tornese, Antoniangela Cocco, Maria Lo Giudice, Michela Matteoli, Eliana Lauranzano, Maria Luisa Malosio, Chiara Adriana Elia, Flavia Lombardo, Flavia Mayer, Maria Puopolo, Stefania Spila Alegiani, Adriano Chiò, Umberto Manera, Cristina Moglia, Andrea Calvo, Paolina Salamone, Giuseppe Fuda, Carlo Colosimo, Cristina Spera, Prabha Cristina Ranchicchio, Giuseppe Stipa, Domenico Frondizi, Christian Lunetta, Valeria Sansone, Claudia Tarlarini, Francesca Gerardi, Vincenzo Silani, Alberto Doretti, Eleonora Colombo, Gianluca Demirtzidis, Gioacchino Tedeschi, Francesca Trojsi, Carla Passaniti, Stefania Ballestrero, Johannes Dorst, Ulrike Weiland, Andrea Fromm, Maximilian Wiesenfarth, Katharina Kandler, Simon Witzel, Markus Otto, Joachim Schuster, Thomas Meyer, André Maier, Dagmar Kettemann, Susanne Petri, Lars Müschen, Camilla Wohnrade, Anastasia Sarikidi, Alma Osmanovic, Julian Grosskreutz, Annekathrin Rödiger, Robert Steinbach, Benjamin Ilse, Uta Smesny, Robert Untucht, René Günther, Maximilian Vidovic, Pamela Shaw, Alexis Collins, Helen Wollff, Theresa Walsh, Lee Tuddenham, Mbombe Kazoka, David White, Stacy Young, Benjamin Thompson, Daniel Madarshahian, Suresh K Chhetri, Amina Chaouch, Carolyn A Young, Heike Arndt, Oliver C Hanemann, Thomas Lambert, Stephane Beltran, Philippe Couratier, Florence Esselin, William Camu, Elisa De, La Cruz, Gwendal Lemasson, Pegah Masrori, Sinead Maguire, Liz Fogarty, Toyosi Atoyebi, Niamh Ní Obáin, Tornese, Paolo, Cocco, Antoniangela, Giudice, Maria Lo, Matteoli, Michela, Lauranzano, Eliana, Malosio, Maria Luisa, Adriana Elia, Chiara, Lombardo, Flavia, Mayer, Flavia, Puopolo, Maria, Alegiani, Stefania Spila, Chiò, Adriano, Manera, Umberto, Moglia, Cristina, Calvo, Andrea, Salamone, Paolina, Fuda, Giuseppe, Colosimo, Carlo, Spera, Cristina, Ranchicchio, Prabha Cristina, Stipa, Giuseppe, Frondizi, Domenico, Lunetta, Christian, Sansone, Valeria, Tarlarini, Claudia, Gerardi, Francesca, Silani, Vincenzo, Doretti, Alberto, Colombo, Eleonora, Demirtzidis, Gianluca, Tedeschi, Gioacchino, Trojsi, Francesca, Passaniti, Carla, Ballestrero, Stefania, Dorst, Johannes, Weiland, Ulrike, Fromm, Andrea, Wiesenfarth, Maximilian, Kandler, Katharina, Witzel, Simon, Otto, Markus, Schuster, Joachim, Meyer, Thomas, Maier, André, Kettemann, Dagmar, Petri, Susanne, Müschen, Lars, Wohnrade, Camilla, Sarikidi, Anastasia, Osmanovic, Alma, Grosskreutz, Julian, Rödiger, Annekathrin, Steinbach, Robert, Ilse, Benjamin, Smesny, Uta, Untucht, Robert, Günther, René, Vidovic, Maximilian, Shaw, Pamela, Collins, Alexis, Wollff, Helen, Walsh, Theresa, Tuddenham, Lee, Kazoka, Mbombe, White, David, Young, Stacy, Thompson, Benjamin, Madarshahian, Daniel, Chhetri, Suresh K, Chaouch, Amina, Young, Carolyn A, Arndt, Heike, Hanemann, Oliver C, Lambert, Thomas, Beltran, Stephane, Couratier, Philippe, Esselin, Florence, Camu, William, De, Elisa, Cruz, La, Lemasson, Gwendal, Masrori, Pegah, Maguire, Sinead, Fogarty, Liz, Atoyebi, Toyosi, Obáin, Niamh Ní, Alberto, Albanese, Albert Christian, Ludolph, Christopher J, Mcdermott, Philippe, Corcia, Philip, Van Damme, Leonard H, Van den Berg, Orla, Hardiman, Gilberto, Rinaldi, Nicola, Vanacore, Brian, Dickie, Study Group, TUDCA-ALS, Lo Giudice, Maria, Luisa Malosio, Maria, Spila Alegiani, Stefania, Cristina Ranchicchio, Prabha, Dorst, Johanne, Otto, Marku, Meyer, Thoma, Müschen, Lar, Collins, Alexi, K Chhetri, Suresh, A Young, Carolyn, C Hanemann, Oliver, Lambert, Thoma, and Ní Obáin, Niamh

Subjects
bile acids, amyotrophic lateral sclerosis, therapy, Neurology, bile acid, clinical trial, phase III, amyotrophic lateral sclerosi, Neurology (clinical), ddc:610
Abstract

BackgroundAmyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative rare disease that affects motor neurons in the brain, brainstem, and spinal cord, resulting in progressive weakness and atrophy of voluntary skeletal muscles. Although much has been achieved in understanding the disease pathogenesis, treatment options are limited, and in Europe, riluzole is the only approved drug. Recently, some other drugs showed minor effects.MethodsThe TUDCA-ALS trial is a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The study aims to enroll 320 patients in 25 centers across seven countries in Europe. Enrolled patients are randomized to one of two treatment arms: TUDCA or identical placebo by oral route. The study measures disease progression during the treatment period and compares it to natural progression during a no-treatment run-in phase. Clinical data and specific biomarkers are measured during the trial. The study is coordinated by a consortium composed of leading European ALS centers.ConclusionThis trial is aimed to determine whether TUDCA has a disease-modifying activity in ALS. Demonstration of TUDCA efficacy, combined with the validation of new biomarkers, could advance ALS patient care.Clinical trial registrationClinicalTrials.gov, identifier: NCT03800524.

Published
2022
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29. Comparison of the ability of the King’s and MiToS staging systems to predict disease progression and survival in amyotrophic lateral sclerosis

Author

Rosanna Tortelli, Pierre-Marie Preux, Marin Benoit, Sanae Lahmadi, M. Copetti, Philippe Couratier, Andrea Fontana, Géraldine Lautrette, Jaime Luna, Giancarlo Logroscino, 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, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Università degli Studi di Bari Aldo Moro, Service de l'Information Médicale et de l'Évaluation [CHU Limoges] (SIME), Laboratoire de Biostatistique et d'Informatique Médicale, and Université de Limoges (UNILIM)

Subjects
Oncology, medicine.medical_specialty, Clinical progression, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Amyotrophic lateral sclerosis, Stage (cooking), King's, Proportional hazards model, business.industry, Amyotrophic Lateral Sclerosis, Disease progression, medicine.disease, Predictive value, MiToS, 3. Good health, Neurology, Cohort, Disease Progression, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), ALS, Prediction ability, business, 030217 neurology & neurosurgery, Cohort study
Abstract

International audience; Background: Assessing clinical progression in amyotrophic lateral sclerosis (ALS) remains a challenge. We evaluated the validity and predictive capabilities of the King’s and Milano-Torino Staging (MiToS) systems in a cohort of patients with ALS to demonstrate their benefit in clinical practice.Methodology: A cohort study was performed by including ALS incident cases in a referral center from 2007 to 2016. The staging systems were determined at time of diagnosis and follow-up. The standardized median times to reach each stage were computed. A multi-state model in the framework of the Cox model evaluated the predictive value of measurements. The survival C-statistic was reported as a measure of prediction ability.Results: Overall, 298 incident cases were included. The King’s and MiToS systems described a progressive increase in the risk of dying with each elapsed stage. However, a lower resolution for late disease description for the King’s system was observed, and late stages overlapped for the MiToS system. Slight variations in the staging systems appeared to improve performance based on validity and prediction abilities: (i) in the King’s (C-statistic ¼ 0.783), by adding a new stage involving the need for both gastrostomy and NIV: (ii) in the MiToS (C-statistic ¼ 0.792), by merging stage 3 and stage 4 into a single stage 3.Conclusion: Both King’s and MiToS are valid systems but have certain limitations. Variations in the staging systems may provide a more suitable framework for describing progression and survival. Further research is needed to evaluate the variations in the staging systems.

Published
2021
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30. Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes

Author

Schramm, Catherine, Charbonnier, Camille, Zaréa, Aline, Lacour, Morgane, Wallon, David, Boland, Anne, Deleuze, Jean-François, Olaso, Robert, Alarcon, Flora, Campion, Dominique, Nuel, Grégory, Nicolas, Gaël, Collaborators Daniela Andriuta, Pierre, Anthony, Sophie, Auriacombe, Anna-Chloé, Balageas, Guillaume, Ballan, Mélanie, Barbay, Emilie, Beaufils, Yannick, Béjot, Serge, Belliard, Marie, Benaiteau, Karim, Bennys, Frédéric, Blanc, Stéphanie, Bombois, Claire Boutoleau Bretonnière, Pierre, Branger, Jasmine, Carlier, Leslie, Cartz-Piver, Pascaline, Cassagnaud, Giovanni, Castelnovo, Christine, Champion, Annabelle, Chaussenot, Mathieu, Ceccaldi, Valérie, Chauviré, Yaohua, Chen, Julien, Cogez, Emmanuel, Cognat, Fabienne, Contegal-Callier, Lea, Corneille, Philippe, Couratier, Hélène, Courtemanche, Benjamin, Cretin, Charlotte, Crinquette, Bernard, Croisille, Benjamin, Dauriat, Sophie, Dautricourt, Vincent de la Sayette, Astrid De Liège, Marie De Verdal, Didier, Deffond, Benoit, Delpont, Florence, Demurger, Vincent, Deramecourt, Céline, Derollez, Mira, Didic, Giulia, Diemert, Elsa, Dionet, Philippe, Diraison, Aude, Doan, Martine Doco Fenzy, Boris, Dufournet, Julien, Dumurgier, Hélène, Durand, Anas, Dutray, Frédérique, Etcharry-Bouyx, Maté, Formaglio, Audrey, Gabelle, Anne, Gainche-Salmon, Jean-Claude, Getenet, Emmanuelle, Ginglinger, Olivier, Godefroy, Mathilde, Graber, Chloé, Gregoire, Stephan, Grimaldi, Julien, Gueniat, Claude, Gueriot, Sophie, Haffen, Lorraine, Hamelin, Didier, Hannequin, Cezara, Hanta, Clémence, Hardy, Geoffroy, Hautecloque, Camille, Heitz, Claire, Hourregue, Thérèse, Jonveaux, Snejana, Jurici, Catia, Khoumri, Lejla, Koric, Pierre, Krolak-Salmon, Pierre, Labauge, Morgane, Lacour, Julien, Lagarde, Hélène-Marie, Lanoiselée, Brice, Laurens, Isabelle Le Ber, Gwenaël Le Guyader, Amélie, Leblanc, Thibaud, Lebouvier, Anas, Lippi, Marie-Anne, Mackowiak, Eloi, Magnin, Cecilia, Marelli, Olivier, Martinaud, Aurélien, Maureille, Emilie, Milongo-Rigal, Sophie, Mohr, Hélène, Mollion, Olivier, Moreaud, Alexandre, Morin, Gaël, Nicolas, Julia, Nivelle, Camille, Noiray, Elisabeth, Ollagnon-Roman, Claire, Paquet, Jérémie, Pariente, Florence, Pasquier, Alexandre, Perron, Nathalie, Philippi, Virginie, Pichon, Vincent, Planche, Céline, Poirsier, Marie, Rafiq, Pauline, Rod-Olivieri, Adeline, Rollin-Sillaire, Carole, Roué-Jagot, Dario, Saracino, Marie, Sarazin, Mathilde, Sauvée, François, Sellal, Lila Sirven Villaros, Christel, Thauvin, Camille, Tisserand, Christophe, Tomasino, Cédric, Turpinat, Laurène Van Damme, Olivier, Vercruysse, Alice, Voilly, Nathalie, Wagemann, David, Wallon, Aline, Zarea, Shahzad, Ahmad, Philippe, Amouyel, Claudine, Berr, Anne, Boland, Paola, Bossu, Femke, Bouwman, Jose, Bras, Dominique, Campion, Camille, Charbonnier, Jordi, Clarimon, Antonio, Daniele, Jean-François, Dartigues, Stéphanie, Debette, Jean-François, Deleuze, Nicola, Denning, Oriol, Dols-Icardo, Nick, C Fox, Daniela, Galimberti, Emmanuelle, Génin, Hans, Gille, Benjamin, Grenier-Boley, Detelina, Grozeva, Rita, Guerreiro, John, J Hardy, Clive, Holmes, Henne, Holstege, Marc, Hulsman, Holger, Hummerich, M Arfan Ikram, M Kamran Ikram, Iris, Jansen, Amit, Kawalia, Robert, Kraaij, Jean-Charles, Lambert, Marc, Lathrop, Afina, W Lemstra, Alberto, Lleo, Lauren, Luckcuck, Marcel M A, M Mannens, Rachel, Marshall, Carlo, Masullo, Simon, Mead, Mecocci, Patrizia, Alun, Meggy, Merel, O Mol, Kevin, Morgan, Benedetta, Nacmias, Penny, J Norsworthy, Pau, Pastor, Olivier, Quenez, Alfredo, Ramirez, Rachel, Raybould, Richard, Redon, Marcel J, T Reinders, Anne-Claire, Richard, Steffi, G Riedel-Heller, Fernando, Rivadeneira, Stéphane, Rousseau, Natalie, S Ryan, Salha, Saad, Pascual, Sanchez-Juan, Philip, Scheltens, Jonathan, M Schott, Davide, Seripa, Daoud, Sie, Rebecca, Sims, Erik, Sistermans, Sandro, Sorbi, Resie van Spaendonk, Gianfranco, Spalleta, Nicćolo, Tesi, Betty, Tijms, André, G Uitterlinden, Wiesje, M van der Flier, Sven, J van der Lee, Cornelia, M van Duijn, Jeroen G, J van Rooij, John, C van Swieten, Pieter, J de Visser, Michael, Wagner, and Julie, Williams

Subjects
Genotype, Membrane Transport Proteins, Penetrance, Lifetime risk, Pedigree, Expectation-maximization algorithm, Settore MED/26 - NEUROLOGIA, Apolipoproteins E, Missing genotypes, Alzheimer Disease, Case-Control Studies, SORL1, Alzheimer, Genetics, Humans, Molecular Medicine, Molecular Biology, LDL-Receptor Related Proteins, APOE, Genetics (clinical)
Abstract

Background Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE-ε4, make such estimations difficult. Methods We proposed to estimate the age-related penetrance of SORL1-LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1-LoF variants, stratified by APOE-ε4, derived from the Rotterdam study (N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1-LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE-ε4-stratified SORL1-LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. Results SORL1-LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among APOE-ε4ε4 carriers only, compared with 56% [40–72%] and 37% [26–51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1-LoF variant carriers in case-control study data. Conclusions We conclude that SORL1-LoF variants should be interpreted in light of APOE genotypes for future clinical applications.

Published
2022
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31. Therapeutic patient education in Alzheimer's disease and related disorders: Clinical experience and perspectives

Author

B. Calvet, M. Chouly, C. Diebolt, L.A. Garçonnot, Philippe Couratier, L. Cartz-Piver, C. Polin, Jean-Pierre Clément, Service de Neurologie [CHU Limoges], CHU Limoges, 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 Psychiatrie [CHU Limoges], Centre de Mémoire de Ressources et de Recherches [Limoges] (CMRR Limoges), and CHU Limoges-CH Esquirol [Limoges] (CH Esquirol)

Subjects
Male, medicine.medical_specialty, Disease, Alzheimer's disease and related disorders, 03 medical and health sciences, 0302 clinical medicine, Cost of Illness, Patient Education as Topic, Alzheimer Disease, Surveys and Questionnaires, Therapeutic patient education, Humans, Medicine, 030212 general & internal medicine, Intensive care medicine, Depression (differential diagnoses), Aged, Aged, 80 and over, Health professionals, business.industry, Self-Management, Cognition, Patient education, Middle Aged, 3. Good health, Chronic disease, Caregivers, Socioeconomic Factors, Neurology, Patient Satisfaction, Depression and anxiety, Chronic Disease, Anxiety, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, France, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

International audience; Therapeutic patient education (TPE) is the process by which health professionals impart information to help patients self-manage their chronic disease: it is an essential part of treatment of long-term diseases and conditions. Memory loss and other cognitive disorders are usually considered as obstacles to TPE for patients with Alzheimer's disease or related disorders (ADRD). Over 100 patients with different forms of ADRD and caregivers have benefited from TPE programs since 2011 at the Limoges University Clinical and Research Memory Center. Participants report better understanding of the disease and improved relationships. TPE may prevent anxiety and depression in patient and in caregivers, and reduce burden of caregivers. General guidelines and perspectives for TPE in ADRD are outlined.

Published
2020
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32. Clinical trials in pediatric ALS: a TRICALS feasibility study

Author

Tessa Kliest, Ruben P.A. Van Eijk, Ammar Al-Chalabi, Alberto Albanese, Peter M. Andersen, Maria Del Mar Amador, Geir BrÅthen, Veronique Brunaud-Danel, Lev Brylev, William Camu, Mamede De Carvalho, Cristina Cereda, Hakan Cetin, Delia Chaverri, Adriano Chiò, Philippe Corcia, Philippe Couratier, Fabiola De Marchi, Claude Desnuelle, Michael A. Van Es, JesÚs Esteban, Massimiliano Filosto, Alberto GarcÍa Redondo, Julian Grosskreutz, Clemens O. Hanemann, Trygve HolmØy, Helle HØyer, Caroline Ingre, Blaz Koritnik, Magdalena Kuzma-Kozakiewicz, Thomas Lambert, Peter N. Leigh, Christian Lunetta, Jessica Mandrioli, Christopher J. Mcdermott, Thomas Meyer, Jesus S. Mora, Susanne Petri, MÓnica Povedano, Evy Reviers, Nilo Riva, Kit C.B. Roes, Miguel Á. Rubio, FranÇois Salachas, Stayko Sarafov, Gianni SorarÙ, Zorica Stevic, Kirsten Svenstrup, Anette Torvin MØller, Martin R. Turner, Philip Van Damme, Lucie A.G. Van Leeuwen, Luis Varona, Juan F. VÁzquez Costa, Markus Weber, Orla Hardiman, Leonard H. Van Den Berg, Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Maurice Wohl Clinical Neuroscience Institut, King‘s College London, King's College Hospital (KCH), Department Neurological Sciences, Milan University, IRCCS Humanitas Clinical Institute, Rozzano, M, Umeå University, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Lille, Ministry of Healthcare of Russian Federation, Department of Neurology, Montpellier CHU, Gui De Chauliac Hospital, Montpellier, Université de Lisbonne, Medizinische Universität Wien = Medical University of Vienna, Hospital Universitario La Paz, Università degli studi di Torino = University of Turin (UNITO), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Epidémiologie des Maladies Chroniques en zone tropicale (EpiMaCT), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-OmégaHealth (ΩHealth), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Service de Neurologie [CHU Limoges], CHU Limoges, Centre référent Sclérose Latérale Amyotrophique et autres maladies du motoneurone [CHU Limoges] (SLA CHU Limoges), Neurology Clinic, University Hospital 'Maggiore della Carità', Novara, Hôpital Pasteur [Nice] (CHU), Centro de Diagnóstico de Enfermedades Moleculares, Dpto. Biol. Mol. Centro de Biología Molecular-SO UAM-CSIC. Universidad Autónoma Madrid, Campus Cantoblanco, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Car, University of Brescia, Lubeck University Hospital, Peninsula Schools of Medicine and Dentistry, Plymouth University, University of Oslo (UiO), Akershus University Hospital [Lørenskog], Telemark Hospital Trust [Skien, Norway], Karolinska Institutet, Department of Neurology, Karolinska University Hospital [Stockholm], University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), Departement de Neurology (MEDICAL UNIVERSITY OF WARSAW), Medical University of Warsaw - Poland, University Hospitals of North Midlands NHS Trust, Royal Stoke Hospital, Stoke-on-Trent, United Kingdom., University of Sussex, University of Modena and Reggio Emilia, Department of Biomedical Sciences, Department of Neuroscience, Academic Neurology Unit, University of Sheffield, Sant Rafael Hospital, Department of Neurology, Hannover Medical School, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, University of Barcelona, Leuven University Hospitals, Division of Neuroscience, San Raffaele Scientific Institute, San Raffaele Scientific Institute, Milan, Italy, Radboud University Medical Center [Nijmegen], IMIM-Hospital del Mar, Generalitat de Catalunya, Medical University of Sofia [Bulgarie], Université de Padoue, Institute of Neurology, Clinical Center of Serbia, University of Belgrade, Belgrade, University of Belgrade [Belgrade], University of Copenhagen = Københavns Universitet (UCPH), Aarhus University Hospital, University of Oxford, Nuffield Department of Clinical Neurosciences, Oxford, UK, University Hospitals Leuven [Leuven], Servicio de Neurología, Hospital de Cruces, Barakaldo, Vizcaya, Neurology Service, Hospital Universitario La Fe, Valencia, Cantonal Hospital St Gallen (KSSG), and Department of Neurology, The Adelaide and Meath Hospital, Trinity College Dublin

Subjects
Adult, Databases, Factual, Neurologi, GENETICS, Clinical Neurology, AMYOTROPHIC-LATERAL-SCLEROSIS, Pediatric amyotrophic lateral sclerosis, pediatric investigation plan, Databases, Prevalence, Humans, clinical trial, clinical trials, ethics, therapy, Child, Feasibility Studies, Europe, Amyotrophic Lateral Sclerosis, Factual, Science & Technology, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Neurology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), Neurosciences & Neurology, Life Sciences & Biomedicine
Abstract

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (

Published
2022
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33. The hypometabolic state: A good predictor of a better prognosis in amyotrophic lateral sclerosis

Author

Nicoletta Guanziroli, Philippe Fayemendy, Philippe Couratier, Nilo Riva, Ettore Corradi, Valeria A. Sansone, Philippe Corcia, Christian Lunetta, Andrea Lizio, Letizia Leocani, Massimo Filippi, Marina Cattaneo, Pierre Jésus, Cattaneo, M., Jesus, P., Lizio, A., Fayemendy, P., Guanziroli, N., Corradi, E., Sansone, V., Leocani, L., Filippi, M., Riva, N., Corcia, P., Couratier, P., Lunetta, C., ASST Grande Ospedale Metropolitano Niguarda, Neuroépidémiologie Tropicale (NET), 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), Service d'Hépato-Gastro-Entérologie et Nutrition [CHU Limoges], CHU Limoges, San Raffaele Hospital, Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Limoges], 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), and Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, medicine.medical_specialty, 030309 nutrition & dietetics, medicine.medical_treatment, 03 medical and health sciences, 0302 clinical medicine, Weight loss, Internal medicine, Weight Loss, medicine, Humans, Amyotrophic lateral sclerosis, Aged, Retrospective Studies, 0303 health sciences, business.industry, Amyotrophic Lateral Sclerosis, Retrospective cohort study, Calorimetry, Indirect, Middle Aged, medicine.disease, Prognosis, Gastrostomy, 3. Good health, Psychiatry and Mental health, Malnutrition, Cohort, Breathing, Hypermetabolism, Body Composition, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Surgery, Female, Neurology (clinical), medicine.symptom, business, Energy Metabolism, 030217 neurology & neurosurgery
Abstract

BackgroundMalnutrition and weight loss are negative prognostic factors for survival in patients with amyotrophic lateral sclerosis (ALS). However, energy expenditure at rest (REE) is still not included in clinical practice, and no data are available concerning hypometabolic state in ALS.ObjectiveTo evaluate in a referral cohort of patients with ALS the prevalence of hypometabolic state as compared with normometabolic and hypermetabolic states, and to correlate it with clinical phenotype, rate of progression and survival.DesignWe conducted a retrospective study examining REE measured by indirect calorimetry in patients with ALS referred to Milan, Limoges and Tours referral centres between January 2011 and December 2017. Hypometabolism and hypermetabolism states were defined when REE difference between measured and predictive values was ≤−10% and ≥10%, respectively. We evaluated the relationship between these metabolic alterations and measures of body composition, clinical characteristics and survival.ResultsEight hundred forty-seven patients with ALS were recruited. The median age at onset was 63.79 years (IQR 55.00–71.17). The male/female ratio was 1.26 (M/F: 472/375). Ten per cent of patients with ALS were hypometabolic whereas 40% were hypermetabolic. Hypometabolism was significantly associated with later need for gastrostomy, non-invasive ventilation and tracheostomy placement. Furthermore, hypometabolic patients with ALS significantly outlived normometabolic (HR=1.901 (95% CI 1.080 to 3.345), p=0.0259) and hypermetabolic (HR=2.138 (95% CI 1.154 to 3.958), p=0.0157) patients.ConclusionHypometabolism in ALS is not uncommon and is associated with slower disease progression and better survival than normometabolic and hypermetabolic subjects. Indirect calorimetry should be performed at least at time of diagnosis because alterations in metabolism are correlated with prognosis.

Published
2022
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36. Reply to the letter from Gazulla et al

Author

Philippe Couratier, Mamede de Carvalho, Christian Lunetta, Patrick Vourc'h, Marie-Hélène Soriani, Susana Pinto, Philippe Corcia, Claude Desnuelle, Marta Gromicho, Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Limoges], CHU Limoges, 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), Centre référent Sclérose Latérale Amyotrophique et autres maladies du motoneurone [CHU Limoges] (SLA CHU Limoges), and Laboratoire de Biochimie et Biologie Moléculaire [Tours]

Subjects
0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Neurology, business.industry, Medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), Theology, business, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience

Published
2022
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37. Spatio-temporal clustering of amyotrophic lateral sclerosis in France: A population-based study

Author

Farid, Boumédiene, Benoît, Marin, Jaime, Luna, Vincent, Bonneterre, William, Camu, Emmeline, Lagrange, Gérard, Besson, Florence, Esselin, Elisa, De La Cruz, Géraldine, Lautrette, Pierre Marie, Preux, and Philippe, Couratier

Abstract

To assess spatial aggregates of amyotrophic lateral sclerosis (ALS) incident cases, using a solid geo-epidemiological statistical method, in France.This population-based study (2003-2011) investigated 47.1 million person-years of follow-up (PYFU). Case ascertainment of incident ALS cases was based on multiple sources (ALS referral centers, hospital centres and health insurance data). Neurologists confirmed all ALS diagnoses. Exhaustiveness was estimated through capture-recapture. Aggregates were investigated in four steps: (a) geographical modelling (standardized incidence ratio (SIR) calculation), (b) analysis of the spatial distribution of incidence (Phothoff-Winttinghill's test, Global Moran's Index, Kulldorf's spatial scan statistic, Local Moran's Index), (c) classification of the level of certainty of spatial aggregates (i.e. definite cluster; probable over-incidence area; possible over-incidence area) and (d) evaluation of the robustness of the results.The standardized incidence of ALS was 2.46/100,000 PYFU (95% CI 2.31-2.63, European population as reference) based on 1199 incident cases. We identified 13 areas of spatial aggregates: one cluster (stable in robustness analysis), five probable over-incidence areas (2 stable in robustness analysis) and seven possible over-incidence areas (including 4 stable areas in robustness analysis). A cluster was identified in the Rhône-Alpes region: 100 observed vs 54.07 expected cases for 2,411,514 PYFU, SIR: 1.85 (95% CI 1.50-2.25).We report here one of the largest investigations of incidence and spatial aggregation of ALS ever performed in a western country. Using a solid methodology framework for case ascertainment and cluster analysis, we identified 13 areas that warrant further investigation.

Published
2021

39. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

Author

Barbier, Mathieu, Camuzat, Agnès, Hachimi, Khalid El, Guegan, Justine, Rinaldi, Daisy, Lattante, Serena, Houot, Marion, Sánchez-Valle, Raquel, Sabatelli, Mario, Antonell, Anna, Molina-Porcel, Laura, Clot, Fabienne, Couratier, Philippe, van der Ende, Emma, van der Zee, Julie, Manzoni, Claudia, Camu, William, Cazeneuve, Cécile, Sellal, François, Didic, Mira, Golfier, Véronique, Pasquier, Florence, Duyckaerts, Charles, Rossi, Giacomina, Bruni, Amalia C, Alvarez, Victoria, Gómez-Tortosa, Estrella, de Mendonça, Alexandre, Graff, Caroline, Masellis, Mario, Nacmias, Benedetta, Oumoussa, Badreddine Mohand, Jornea, Ludmila, Forlani, Sylvie, Van Deerlin, Viviana, Rohrer, Jonathan D, Gelpi, Ellen, Rademakers, Rosa, Van Swieten, John, Le Guern, Eric, Van Broeckhoven, Christine, Ferrari, Raffaele, Génin, Emmanuelle, Brice, Alexis, Ber, Le, Isabelle Alexis Brice, Sophie, Auriacombe, Serge, Belliard, Anne, Bertrand, Anne, Bissery, Fre ́ de, ́ ric Blanc, Marie-Paule, Boncoeur, Ste, ́ phanie Bombois, Claire Boutoleau-Bretonnie` re, Agne`, s Camuzat, Mathieu, Ceccaldi, Marie, Chupin, Philippe, Couratier, Olivier, Colliot, Vincent, Deramecourt, Mira, Didic, Bruno, Dubois, Charles, Duyckaerts, Fre ́ de, ́ rique Etcharry-Bouyx, Aure, ́ lie Guignebert-Funkiewiez, Maı ̈te, ́ Formaglio, ́ ronique Golfier, Ve, Marie-Odile, Habert, Didier, Hannequin, Lucette, Lacomblez, Julien, Lagarde, ́ raldine Lautrette, Ge, Isabelle Le Ber, Benjamin Le Toullec, Richard, Levy, Marie-Anne, Mackowiak, Bernard-Franc ̧ois Michel, Florence, Pasquier, Thibaud, Lebouvier, Carole Roue, ́ -Jagot, Christel Thauvin- Robinet, Catherine, Thomas-Anterion, Je ́ re, ́ mie Pariente, Franc ̧ois Salachas, Sabrina, Sayah, Franc ̧ois Sellal, Assi-Herve, ́ Oya, Daisy, Rinaldi, Adeline, Rollin-Sillaire, Martine, Vercelletto, David, Wallon, Armelle, Rametti-Lacroux, Raffaele, Ferrari, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Adaikalavan, Ramasamy, Kwok, John B. J., Carol Dobson- Stone, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Olivier, Piguet, Lauren, Bartley, Elizabeth, Thompson, Isabel Herna, ́ ndez, Agustı ́n Ruiz, Merce`, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Cairns, Nigel J., Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigi, Forloni, Diego, Albani, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, ́ n, Jordi Clarimo, Alberto Lleo, ́, Rafael, Blesa, Maria Landqvist Waldo, ̈, Karin, Nilsson, Christer, Nilsson, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Jordan, Grafman, Morris, Christopher M., Johannes, Attems, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Pietro, Pietrini, Edward, Uey, Wassermann, Eric M., Atik, Baborie, Evelyn, Jaros, Tierney, Michael C., Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robert, Perneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Ekaterina, Rogaeva, Peter St George-Hyslop, Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, Rowe, James B., Schlachetzki, Johannes C. M., James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Van Deerlin, Vivianna M., Murray, Grossman, Trojanowski, John Q., Julie van der Zee, Christine Van Broeckhoven, Cappa, Stefano F., Isabelle, Leber, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Nielsen, Jørgen E., Hjermind, Lena E., Matthias, Riemenschneider, Manuel, Mayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Maria Grazia Spillantini, Morris, Huw R., Patrizia, Rizzu, Peter, Heutink, Snowden, Julie S., Sara, Rollinson, Anna, Richardson, Alexander, Gerhard, Bruni, Amalia C., Raffaele, Maletta, Francesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., David, Knopman, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Howard, Rosen, van Swieten, John C., Dopper, Elise G. P., Harro, Seelaar, Pijnenburg, Yolande A. L., Philip, Scheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Puca, Annibale A., Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolo, Sorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Adeline, Rollin, Dimitrios, Kapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Singleton, Andrew B., John, Hardy, Parastoo, Momeni., Neurology, Amsterdam Neuroscience - Neurodegeneration, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Dupuytren [CHU Limoges], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Center for Molecular Neurology (VIB-UAntwerp), University of Antwerp (UA), University College of London [London] (UCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Yves le Foll, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Hospital Central de Asturias, Institute of Health Research of Principado de Asturias (ISPA), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Karolinska University Hospital [Stockholm], Sunnybrook Research Institute [Toronto] (SRI), Sunnybrook Health Sciences Centre, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione Don Carlo Gnocchi, Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), The French clinical and genetic Research network on FTLD/FTLD-ALS and PREVDEMALS, The International Frontotemporal Dementia Genomics Consortium, The European Early Onset Dementia (EU -EOD) Consortium, Brainbank Neuro-CEB Neuropathology Network, and Neurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPS

Subjects
Adult, Male, TDP-43, C9orf72, SLITRK2, amyotrophic lateral sclerosis, frontotemporal dementia, Nerve Tissue Proteins, Settore MED/03 - GENETICA MEDICA, Polymorphism, Single Nucleotide, Cohort Studies, Genes, X-Linked, 80 and over, Medicine, Dementia, Humans, Allele, Age of Onset, Polymorphism, Aged, Aged, 80 and over, biology, C9orf72 Protein, business.industry, Membrane Proteins, MESH: Frontotemporal Lobar Degeneration / epidemiology, Frontotemporal Lobar, Degeneration / genetics, Genes, X-Linked / genetics, Genome-Wide Association Study / methods, Frontotemporal lobar degeneration, Single Nucleotide, Middle Aged, X-Linked, medicine.disease, Amyotrophic lateral sclerosis, Minor allele frequency, Genes, Immunology, Synaptophysin, biology.protein, Female, MESH: Adult, C9orf72 Protein / genetics, Frontotemporal Lobar Degeneration / diagnosis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, Neurology (clinical), MESH: Humans, Membrane Proteins / genetics, Nerve Tissue Proteins / genetics, Polymorphism, Single Nucleotide / genetics, Age of onset, Frontotemporal Lobar Degeneration, business, Frontotemporal dementia, Genome-Wide Association Study
Abstract

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

Published
2021
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40. Clinical management and disease-modifying treatment for amyotrophic lateral sclerosis in African hospital centers: the TROPALS study

Author

Lamia Ali Pacha, Anna Modji Basse, Noudy Sengxeu, Jaime Luna, Dieudonné Gnonlonfoun, Philippe Couratier, Meriem Tazir, Leila Ait Aissa, Jeremy Jost, M Belo, Riadh Gouider, Franclo Henning, Dismand Houinato, Ousmane Cisse, Mendinatou Agbétou, Aa Koffi Balogou, Damelan Kombate, Mouhamadou Diagana, Pierre-Marie Preux, Marin Benoit, Thierry Agba, Athanase Millogo, Bello Hamidou, Imen Kacem, Neuroépidémiologie Tropicale (NET), 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), Service de Pharmacie Centrale [CHU Limoges], CHU Limoges, Service de Neurologie, C.H.U Mustapha Bacha, Place du 1er Mai, 16000 Alger, Algeria, Hopital de Razi - Razi Hospital [Tunis], Stellenbosch University, CHNU Fann Dakar, Service de Neurologie, CHU Campus Université de Lomé, Service de Neurologie, CHU Campus Université de Lomé-Service de Neurologie, CHU Campus Université de Lomé, Centre National Hospitalier Universitaire Hubert K. Maga de Cotonou (CNHU-HKM), Laboratory of Chronic and Neurological Diseases Epidemiology (LEMACEN), University of Abomey Calavi (UAC), Université Joseph Ki-Zerbo [Ouagadougou] (UJZK), Université de Lomé [Togo], Service de l'Information Médicale et de l'Évaluation [CHU Limoges] (SIME), Laboratoire de Biostatistique et d'Informatique Médicale, Université de Limoges (UNILIM), and Service de Neurologie [CHU Limoges]

Subjects
medicine.medical_specialty, availability, Disease, 03 medical and health sciences, 0302 clinical medicine, Multidisciplinary approach, Health care, medicine, Humans, Amyotrophic lateral sclerosis, 030304 developmental biology, 0303 health sciences, affordability, business.industry, medicine.disease, riluzole, Hospitals, 3. Good health, Riluzole, Neurology, Who guidelines, Family medicine, Africa, Observational study, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), business, 030217 neurology & neurosurgery, management, medicine.drug
Abstract

International audience; Objective: To assess the availability of health workers and medications for clinical management of amyotrophic lateral sclerosis (ALS) in African hospital centers. Availability and affordability analyses of disease-modifying treatments were performed. Methods: A multicenter observational study involving African hospitals was conducted. A standard questionnaire was developed based on the European Federation of the Neurological Societies (EFNS) guidelines. We collected data on multidisciplinary care and availability of medicines. The availability and affordability were evaluated according to the WHO guidelines. Results: Nine hospital centers from eight African countries participated. We observed a low degree of implementation of multidisciplinary care in ALS management. Riluzole was only available in centers from South Africa, Senegal, Tunisia, and Togo. This treatment was unaffordable and the adjusted price was highly variable among countries. The cost of riluzole was partly or fully covered by patients, which implies a substantial economic burden. Conclusion: Our findings strengthen the need to promote multidisciplinary care in the clinical management of ALS in Africa. Disease-modifying medication should be both available and affordable. Local and international collaboration is needed to improve ALS health care access in Africa.

Published
2021
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41. Loss of nucleoporin Nup50 is a risk factor for amyotrophic lateral sclerosis

Author

Jan H. Veldink, Edor Kabashi, Sylvie Dirrig-Grosch, Peter M Andersen, Najwa Ouali Alami, Luc Dupuis, Kirsten Sieverding, Axel Freischmidt, Natalia Mora, Albert C. Ludolph, Tobias M. Boeckers, Markus Margelisch, Philippe Couratier, Francesco Roselli, François Muratet, Andreas Sommacal, Chantal Sellier, Géraldine Lautrette, Erik Storkebaum, Markus Weber, Nick H.M. van Bakel, Stéphane Dieterlé, Stéphanie Millecamps, Kristel R. van Eijk, Jochen H. Weishaupt, Alberto Catanese, Kathrin Muller, Salim Megat, Xhuljana Mingaj, Christoph Neuwirth, Jason Sanogo, Hortense de Calbiac, and Deniz Yilmazer-Hanke

Subjects
Genetics, BCS1L, RNA splicing, Gene expression, medicine, RNA-binding protein, Genome-wide association study, Nucleoporin, Amyotrophic lateral sclerosis, Biology, medicine.disease, Gene
Abstract

The genetic basis of amyotrophic lateral sclerosis (ALS) is still incompletely understood. Using two independent genetic strategies, we show here that a large part of ALS heritability lies in genes expressed in inhibitory and excitatory neurons, especially at splicing sites regulated by a defined set of RNA binding proteins including TDP-43 and FUS. We conducted a transcriptome wide association study (TWAS) and identified 59 loci associated with ALS, including 14 previously identified genes, some of them not previously reaching significance in genome wide association studies. Among the 45 novel genes, several genes are involved in pathways known to be affected in ALS such as mitochondrial metabolism (including ATP5H, ATP5D, BCS1L), proteostasis (including COPS7A, G2E3, TMEM175, USP35) or gene expression and RNA metabolism (including ARID1B, ATXN3, PTBP2, TAF10). Interestingly, decreased expression of NUP50, a constrained gene encoding a nuclear pore basket protein, was associated with ALS in TWAS (Zscore = −4, FDR = 0.034). 11 potentially pathogenic variants (CADD score > 20) in 23 patients were identified in the NUP50 gene, most of them in the region of the protein mediating interaction with Importin alpha, and including 2 frameshift mutations. In cells from two patients carrying NUP50 variants, we showed decreased levels of NUP50 protein. Importantly, knocking down Nup50 led to increased neuronal death associated with p62 and nucleoporin inclusions in cultured neurons, and motor defects in Drosophila and zebrafish models. In all, our study identifies alterations in splicing in neurons as a critical pathogenic process in ALS, uncovers several new loci potentially contributing to ALS missing heritability, and provides genetic evidence linking nuclear pore defects to ALS.

Published
2021
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42. Familial clustering of primary lateral sclerosis and amyotrophic lateral sclerosis: Supplementary evidence for a continuum

Author

Marie-Hélène Soriani, Philippe Corcia, Christian Lunetta, Patrick Vourc'h, Philippe Couratier, Susana Pinto, Mamede de Carvalho, Claude Desnuelle, Marta Gromicho, UMR U 1253, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA 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, Centre référent Sclérose Latérale Amyotrophique et autres maladies du motoneurone [CHU Limoges] (SLA CHU Limoges), Laboratoire de Biochimie [CHU Tours], Université de Lisbonne, Hôpital Pasteur [Nice] (CHU), and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)

Subjects
amyotrophic lateral sclerosis, phenotype, Familial clustering, Disease, Lower motor neuron, 03 medical and health sciences, 0302 clinical medicine, medicine, genetics, 030212 general & internal medicine, Amyotrophic lateral sclerosis, 10. No inequality, Primary Lateral Sclerosis, business.industry, TREM2, Motor neuron, medicine.disease, medicine.anatomical_structure, Neurology, Disease Presentation, familial clustering, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), primary lateral sclerosis, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; Background and purpose: Primary lateral sclerosis (PLS) is a motor neuron disorder characterized by a pure upper motor neuron degeneration in the bulbar and spinal regions. The key difference with amyotrophic lateral sclerosis (ALS) is the lower motor neuron system integrity. Despite important literature on this disease, the pathophysiology of PLS remains unknown, and the link with ALS still balances between a continuum and a separate entity from ALS. Methods: We report nine families in which both PLS and ALS cases occurred, in general among first-degree relatives. Results: The patients with PLS and ALS had a typical disease presentation. Genetic studies revealed mutations in SQSMT1, TBK1, and TREM2 genes in two PLS patients and one ALS patient. Conclusions: These results strongly support a phenotypic continuum between PLS and ALS.

Published
2021
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43. Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis

Author

Sai Zhang, Johnathan Cooper-Knock, Annika K. Weimer, Minyi Shi, Tobias Moll, Jack N.G. Marshall, Calum Harvey, Helia Ghahremani Nezhad, John Franklin, Cleide dos Santos Souza, Ke Ning, Cheng Wang, Jingjing Li, Allison A. Dilliott, Sali Farhan, Eran Elhaik, Iris Pasniceanu, Matthew R. Livesey, Chen Eitan, Eran Hornstein, Kevin P. Kenna, Jan H. Veldink, Laura Ferraiuolo, Pamela J. Shaw, Michael P. Snyder, Ian Blair, Naomi R. Wray, Matthew Kiernan, Miguel Mitne Neto, Adriano Chio, Ruben Cauchi, Wim Robberecht, Philip van Damme, Philippe Corcia, Philippe Couratier, Orla Hardiman, Russell McLaughin, Marc Gotkine, Vivian Drory, Nicola Ticozzi, Vincenzo Silani, Leonard H. van den Berg, Mamede de Carvalho, Jesus S. Mora Pardina, Monica Povedano, Peter Andersen, Markus Weber, Nazli A. Başak, Ammar Al-Chalabi, Chris Shaw, Karen E. Morrison, John E. Landers, Jonathan D. Glass, and Project MinE ALS Sequencing Consortium

Subjects
Motor Neurons, Cell Death, General Neuroscience, Amyotrophic Lateral Sclerosis, Induced Pluripotent Stem Cells, Cytoskeletal Proteins, Amyotrophic lateral sclerosis -- Diagnosis, Genes, Machine learning, Genetics, Humans, Epigenetics, Nervous system -- Degeneration, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study
Abstract

Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed a machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling of motor neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes that represent a 5-fold increase in recovered heritability. Extensive conservation, transcriptome, network, and rare variant analyses demonstrated the functional significance of candidate genes in healthy and diseased motor neurons and brain tissues. Genetic convergence between common and rare variation highlighted KANK1 as a new ALS gene. Reproducing KANK1 patient mutations in human neurons led to neurotoxicity and demonstrated that TDP-43 mislocalization, a hallmark pathology of ALS, is downstream of axonal dysfunction. RefMap can be readily applied to other complex diseases., peer-reviewed

Published
2021

44. The future of ALS might move towards Genetic Therapy

Author

Philippe Couratier, Philippe Corcia, Patrick Vourc'h, 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, and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
business.industry, Amyotrophic Lateral Sclerosis, MEDLINE, Computational biology, Genetic Therapy, Genetic therapy, 03 medical and health sciences, 0302 clinical medicine, Text mining, Neurology, Medicine, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 030212 general & internal medicine, Neurology (clinical), business, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2021
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45. Sclérose latérale amyotrophique : orientations du bilan génétique chez les patients et apparentés

Author

Philippe Couratier, Neuroépidémiologie Tropicale (NET), 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), Service de Neurologie [CHU Limoges], and CHU Limoges

Subjects
03 medical and health sciences, 0302 clinical medicine, Neurology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 030212 general & internal medicine, Neurology (clinical), SLA, Génétique, Slérose, 030217 neurology & neurosurgery
Abstract

International audience; L’approche clinique des patients atteints de sclérose latérale amyotrophique (SLA) a été largement modifiée par l’identification de nouveaux gènes, la détection de mutations génétiques chez des patients apparemment sporadiques, et la découverte de la relation génétique et clinique stricte entre la SLA et la démence frontotemporale (DFT). En conséquence, les cliniciens sont de plus en plus confrontés au dilemme de la gestion du conseil et des tests génétiques, tant pour les patients atteints de SLA que pour leurs proches. Sur la base de la littérature existante sur la génétique de la SLA et d’autres maladies à déclenchement tardif mettant la vie en danger, la proposition d’un dépistage systématique de tous les patients atteints de SLA mérite d’être discutée. Les tests génétiques devraient être proposés aux patients atteints de SLA dont un parent au premier ou au second degré est atteint de SLA, de FTD ou des deux, et devraient être discutés avec tous les autres patients atteints de SLA, mais pas proposés à ces derniers, en mettant l’accent sur ses principales incertitudes. Actuellement, les tests génétiques ne devraient pas être proposés aux sujets à risque asymptomatiques, sauf s’ils en font la demande ou s’ils sont inscrits à des programmes de recherche. Le conseil génétique dans la SLA doit tenir compte des incertitudes sur la pathogénicité et la pénétrance de certaines mutations génétiques, de la présence possible de mutations de différents gènes chez un même individu, de la faible corrélation génotypique/phénotypique dans la plupart des gènes de la SLA et de la pléiotropie phénotypique de certains gènes. Bien que les implications psychologiques, sociales et éthiques des tests génétiques soient encore relativement inexplorées dans la SLA, il pourrait être suggéré un conseil multidisciplinaire qui aborde toutes les questions pertinentes, y compris la divulgation des résultats des tests aux membres de la famille et le risque de discrimination génétique.

Published
2021
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46. Sclérose latérale amyotrophique et ethnicité

Author

Pierre-Marie Preux, Philippe Couratier, Jaime Luna, Neuroépidémiologie Tropicale (NET), 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), Service de l'Information Médicale et de l'Évaluation [CHU Limoges] (SIME), CHU Limoges, Laboratoire de Biostatistique et d'Informatique Médicale, Université de Limoges (UNILIM), and Service de Neurologie [CHU Limoges]

Subjects
Épidémiologie, Neurology, Origine ancestrale, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), Sclérose Latérale Amyotrophique
Abstract

International audience; La sclérose latérale amyotrophique (SLA) est une maladie neurodégénérative fatale. Les travaux scientifiques suggèrent que l’ethnicité et l’origine ancestrale influencent le risque de développer la maladie. L’ethnicité peut prendre en compte les caractéristiques sociales, culturelles ainsi que les générations antérieures. L’origine ancestrale se réfère à un groupe d’individus qui partagent un profil génétique commun, et dont la fréquence d’allèles dans certains loci diffèrent de celle d’autres populations. Les preuves épidémiologiques qui soutiennent l’hypothèse d’une relation entre l’ethnicité et la SLA sont :– La variabilité géographique de l’incidence : Une méta-analyse ne tenant compte que des études en population générale a démontré que l’incidence était homogène parmi les populations d’Europe, d’Amérique du Nord et de Nouvelle-Zélande. Cependant, des différences ont été identifiées entre les populations d’Europe et d’Asie. Parmi les études, une hétérogénéité a été identifiée et a été expliquée par les sous-continents.– L’hétérogénéité entre les groupes ethniques issus d’une même zone géographique : Des données provenant de populations multiethniques, principalement des États-Unis, ont montré une incidence plus élevée de SLA chez la population caucasienne par rapport à la non-caucasienne. Ces résultats concordent avec des études réalisées en Amérique latine (Cuba) et en Afrique (Afrique du Sud). De plus, une incidence plus faible a été observée chez les populations métisses et indigènes aux Etats-Unis et en Amérique Latine.– La diversité génétique entre les populations : La prévalence des variants génétiques associés à la SLA diffère d’une population à l’autre. L’expansion répétée de C9orf72 est la variante génétique la plus fréquente en Europe. A contrario, elle est beaucoup moins fréquente en Asie et seulement quelques patients SLA portant cette expansion en Amérique latine.Une forte collaboration internationale est nécessaire pour fournir des données fiables sur la SLA dans différentes populations et régions géographiques. Ce travail va ainsi permettre de mieux comprendre les interactions complexes existant entre la prédisposition génétique et les facteurs environnementaux au sein des groupes ethniques.

Published
2021
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47. Therapeutic news in ALS

Author

Salah Eddine Bakkouche, Philippe Couratier, Stéphane Beltran, Philippe Corcia, 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, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), 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), and Grelier, Elisabeth

Subjects
Drug, Oncology, medicine.medical_specialty, Weakness, media_common.quotation_subject, Disease, Therapeutic-clinical trials, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, MESH: Riluzole, Internal medicine, medicine, Edaravone, Humans, 030212 general & internal medicine, Amyotrophic lateral sclerosis, MESH: Amyotrophic Lateral Sclerosis, media_common, Motor Neurons, MESH: Genetic Therapy, Riluzole, MESH: Humans, business.industry, Amyotrophic Lateral Sclerosis, Genetic Therapy, Motor neuron, Amyotrophy, medicine.disease, 3. Good health, medicine.anatomical_structure, Neurology, chemistry, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, MESH: Motor Neurons, medicine.drug
Abstract

International audience; Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by death of motor neurons in the cortex and the spinal cord. This loss of motor neurons causes progressive weakness and amyotrophy. To date, the median duration of survival in patients with ALS, from first symptoms to death, is estimated to be 36 months. Currently the treatment is limited to two options: riluzole which prolongs survival for a few months and edaravone which is available in only a few countries and also has a small impact on disease progression. There is an urgent need for more effective drugs in this disease to significantly improve progression. Over the last 30 years, all trials have failed to find a curative drug for ALS. This is due, partially, to the heterogeneity of the clinical features and the pathophysiology of motor neuron death. We present in this review the various treatment options currently being developed for ALS, with an emphasis on the range of therapeutic approaches being explored, from old drugs tested in a new indication to innovative drugs obtained via biotechnology or gene therapy.

Published
2021
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48. Split-hand and split-limb phenomena in amyotrophic lateral sclerosis: pathophysiology, electrophysiology and clinical manifestations

Author

P.-F. Pradat, Steve Vucic, Peter Bede, Mamede de Carvalho, Philippe Corcia, Philippe Couratier, Repositório da Universidade de Lisboa, Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Trinity College Dublin, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Limoges], CHU Limoges, 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), Westmead Hospital [Sydney], The University of Sydney, Universidade de Lisboa = University of Lisbon (ULISBOA), Hospital de Santa Maria [Lisboa], Grelier, Elisabeth, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Universidade de Lisboa (ULISBOA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, Neurophysiology, Action Potentials, 03 medical and health sciences, Clinical, 0302 clinical medicine, medicine, Humans, Motor neuron disease, Amyotrophic lateral sclerosis, neurophysiol, Motor Neurons, business.industry, Amyotrophic Lateral Sclerosis, Progressive neurodegenerative disorder, medicine.disease, Pathophysiology, Clinical neurology, Psychiatry and Mental health, Electrophysiology, 030104 developmental biology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Nerve Degeneration, Lower motor neuron degeneration, Surgery, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), Atrophy, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ., Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting the upper and lower motor neurons. A key clinical feature of ALS is the absence of accurate, early-stage diagnostic indicators. 'Split-hand syndrome' was first described in ALS at the end of the last century and a considerable body of literature suggests that the split-hand phenomenon may be an important clinical feature of ALS. Considering the published investigations, it is conceivable that the 'split-hand syndrome' results from the associated upper and lower motor neuron degeneration, whose interaction remains to be fully clarified. Additionally, other split syndromes have been described in ALS involving upper or lower limbs, with a nuanced description of clinical and neurophysiological manifestations that may further aid ALS diagnosis. In this review, we endeavour to systematically present the spectrum of the 'split syndromes' in ALS from a clinical and neurophysiology perspective and discuss their diagnostic and pathogenic utility.

Published
2021
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49. Epidemiological and genetic features of amyotrophic lateral sclerosis in Latin America and the Caribbean: a systematic review

Author

Jaime Luna, Pierre-Marie Preux, Philippe Couratier, Daniells Erazo, Farid Boumediene, 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 l'Information Médicale et de l'Évaluation [CHU Limoges] (SIME), CHU Limoges, Laboratoire de Biostatistique et d'Informatique Médicale, Université de Limoges (UNILIM), and Service de Neurologie [CHU Limoges]

Subjects
SciELO, medicine.medical_specialty, Latin Americans, MEDLINE, Disease, survival, 03 medical and health sciences, 0302 clinical medicine, Epidemiology, medicine, Ethnicity, Humans, genetics, Amyotrophic lateral sclerosis, clinical characteristics, business.industry, Incidence (epidemiology), Incidence, Amyotrophic Lateral Sclerosis, medicine.disease, 3. Good health, Latin America, Neurology, Caribbean Region, Observational study, epidemiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), business, 030217 neurology & neurosurgery, Demography
Abstract

International audience; Introduction: Heterogeneity of amyotrophic lateral sclerosis (ALS) has been suggested in terms of epidemiology, phenotypes and genetics between geographic areas and populations. However, there is limited information in Latin America. We conducted a systematic review that aimed to describe the epidemiology, frequency of genetic mutations, clinical characteristics and survival of ALS patients in this region. Methods: We reviewed Medline, Scopus, Scielo and LILACS databases up to April 2020. The search terms "Amyotrophic Lateral Sclerosis" or "Motor Neuron Disease" were used in combination with the list of Latin American countries from the United Nations. All observational studies were included. A methodological overview was performed using the principles of descriptive epidemiology. Results: Overall, 1364 publications were identified and 36 studies were selected, covering 13 Latin American countries. According to the original reports, ALS occurrence varied among countries with a standardized incidence ranging from 0.3 per 100,000 person-years follow up (PYFU) in Ecuador to 3.6 per 100,000 PYFU in Uruguay. A low proportion of the C9orf72 repeat expansion was reported in Cuba and Brazil. We identified age at onset between 50 and 60 years. Survival time was higher than 40 months in half of the studies. Data from multiethnic populations reported a higher risk of developing ALS in Caucasians compared to admixed and Black populations. Conclusion: This review provides a perspective of ALS variability across Latin America and highlights specific differences when comparing to Europe and North America. However, we cannot draw firm conclusions because of different methodological concerns within the studies.

Published
2021
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50. Plasma NfL levels and longitudinal change rates in

Author

Dario, Saracino, Karim, Dorgham, Agnès, Camuzat, Daisy, Rinaldi, Armelle, Rametti-Lacroux, Marion, Houot, Fabienne, Clot, Philippe, Martin-Hardy, Ludmila, Jornea, Carole, Azuar, Raffaella, Migliaccio, Florence, Pasquier, Philippe, Couratier, Sophie, Auriacombe, Mathilde, Sauvée, Claire, Boutoleau-Bretonnière, Jérémie, Pariente, Mira, Didic, Didier, Hannequin, David, Wallon, Olivier, Colliot, Bruno, Dubois, Alexis, Brice, Richard, Levy, and Sylvie, Forlani

Subjects
Adult, Aged, 80 and over, Male, C9orf72 Protein, Amyotrophic Lateral Sclerosis, Middle Aged, Progranulins, Neurofilament Proteins, Frontotemporal Dementia, Disease Progression, Humans, Female, Neurogenetics, Aged
Abstract

Objective Neurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages. Methods We analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical–genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index. Results pNfL levels increased with age in controls, from ~5 to~18 pg/mL (p

Published
2021

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