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1. 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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2. 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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3. MicroRNA signatures in genetic frontotemporal dementia and amyotrophic lateral sclerosis

Author: Virgilio Kmetzsch, Morwena Latouche, Dario Saracino, Daisy Rinaldi, Agnès Camuzat, Thomas Gareau, the French Research Network on FTD/ALS, Isabelle Le Ber, Olivier Colliot, and Emmanuelle Becker
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Objective MicroRNAs are promising biomarkers of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), but discrepant results between studies have so far hampered their use in clinical trials. We aim to assess all previously identified circulating microRNA signatures as potential biomarkers of genetic FTD and/or ALS, using homogeneous, independent validation cohorts of C9orf72 and GRN mutation carriers. Methods 104 individuals carrying a C9orf72 or a GRN mutation, along with 31 controls, were recruited through the French research network on FTD/ALS. All subjects underwent blood sampling, from which circulating microRNAs were extracted. We measured differences in the expression levels of 65 microRNAs, selected from 15 published studies about FTD or ALS, between 31 controls, 17 C9orf72 presymptomatic subjects, and 29 C9orf72 patients. We also assessed differences in the expression levels of 30 microRNAs, selected from five studies about FTD, between 31 controls, 30 GRN presymptomatic subjects, and 28 GRN patients. Results More than half (35/65) of the selected microRNAs were differentially expressed in the C9orf72 cohort, while only a small proportion (5/30) of microRNAs were differentially expressed in the GRN cohort. In multivariate analyses, only individuals in the C9orf72 cohort could be adequately classified (ROC AUC up to 0.98 for controls versus presymptomatic subjects, 0.94 for controls versus patients, and 0.77 for presymptomatic subjects versus patients) with some of the signatures. Interpretation Our results suggest that previously identified microRNAs using sporadic or mixed cohorts of FTD and ALS patients could potentially serve as biomarkers of C9orf72‐associated disease, but not GRN‐associated disease.
Published: 2022
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4. Disease Progression Score Estimation From Multimodal Imaging and MicroRNA Data Using Supervised Variational Autoencoders.

Author: Virgilio Kmetzsch, Emmanuelle Becker, Dario Saracino, Daisy Rinaldi, Agnès Camuzat, Isabelle Le Ber, and Olivier Colliot
Published: 2022
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5. Early neurotransmitters changes in prodromal frontotemporal dementia: A GENFI study

Author: Enrico Premi, Marta Pengo, Irene Mattioli, Valentina Cantoni, Juergen Dukart, Roberto Gasparotti, Emanuele Buratti, Alessandro Padovani, Martina Bocchetta, Emily G. Todd, Arabella Bouzigues, David M. Cash, Rhian S. Convery, Lucy L. Russell, Phoebe Foster, David L. Thomas, John C. van Swieten, Lize C. Jiskoot, Harro Seelaar, Daniela Galimberti, Raquel Sanchez-Valle, Robert Laforce, Jr, Fermin Moreno, Matthis Synofzik, Caroline Graff, Mario Masellis, Maria Carmela Tartaglia, James B. Rowe, Kamen A. Tsvetanov, Rik Vandenberghe, Elizabeth Finger, Pietro Tiraboschi, Alexandre de Mendonça, Isabel Santana, Chris R. Butler, Simon Ducharme, Alexander Gerhard, Johannes Levin, Markus Otto, Sandro Sorbi, Isabelle Le Ber, Florence Pasquier, Jonathan D. Rohrer, Barbara Borroni, Aitana Sogorb Esteve, Carolin Heller, Caroline V. Greaves, Henrik Zetterberg, Imogen J. Swift, Kiran Samra, Rachelle Shafei, Carolyn Timberlake, Thomas Cope, Timothy Rittman, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Vittoria Borracci, Giacomina Rossi, Giorgio Giaccone, Giuseppe Di Fede, Paola Caroppo, Sara Prioni, Veronica Redaelli, David Tang-Wai, Ekaterina Rogaeva, Miguel Castelo-Branco, Morris Freedman, Ron Keren, Sandra Black, Sara Mitchell, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Jackie Poos, Janne M. Papma, Lucia Giannini, Rick van Minkelen, Yolande Pijnenburg, Benedetta Nacmias, Camilla Ferrari, Cristina Polito, Gemma Lombardi, Valentina Bessi, Michele Veldsman, Christin Andersson, Hakan Thonberg, Linn Öijerstedt, Vesna Jelic, Paul Thompson, Tobias Langheinrich, Albert Lladó, Anna Antonell, Jaume Olives, Mircea Balasa, Nuria Bargalló, Sergi Borrego-Ecija, Ana Verdelho, Carolina Maruta, Catarina B. Ferreira, Gabriel Miltenberger, Frederico Simões do Couto, Alazne Gabilondo, Ana Gorostidi, Jorge Villanua, Marta Cañada, Mikel Tainta, Miren Zulaica, Myriam Barandiaran, Patricia Alves, Benjamin Bender, Carlo Wilke, Lisa Graf, Annick Vogels, Mathieu Vandenbulcke, Philip Van Damme, Rose Bruffaerts, Koen Poesen, Pedro Rosa-Neto, Serge Gauthier, Agnès Camuzat, Alexis Brice, Anne Bertrand, Aurélie Funkiewiez, Daisy Rinaldi, Dario Saracino, Olivier Colliot, Sabrina Sayah, Catharina Prix, Elisabeth Wlasich, Olivia Wagemann, Sandra Loosli, Sonja Schönecker, Tobias Hoegen, Jolina Lombardi, Sarah Anderl-Straub, Adeline Rollin, Gregory Kuchcinski, Maxime Bertoux, Thibaud Lebouvier, Vincent Deramecourt, Beatriz Santiago, Diana Duro, Maria João Leitão, Maria Rosario Almeida, Miguel Tábuas-Pereira, and Sónia Afonso
Subjects: Frontotemporal dementia, Frontotemporal lobar degeneration, Genes, Magnetic resonance imaging, Positron emission tomography, Neurotransmitters, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Background: Neurotransmitters deficits in Frontotemporal Dementia (FTD) are still poorly understood. Better knowledge of neurotransmitters impairment, especially in prodromal disease stages, might tailor symptomatic treatment approaches. Methods: In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of Magnetic Resonance Imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission.We included 392 mutation carriers (157 GRN, 164 C9orf72, 71 MAPT), together with 276 non-carrier cognitively healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in mutation carriers (relative to HC) are correlated with specific neurotransmitter systems in prodromal (CDR® plus NACC FTLD = 0.5) and in symptomatic (CDR® plus NACC FTLD≥1) FTD. Results: In prodromal stages of C9orf72 disease, voxel-based brain changes were significantly associated with spatial distribution of dopamine and acetylcholine pathways; in prodromal MAPT disease with dopamine and serotonin pathways, while in prodromal GRN disease no significant findings were reported (p
Published: 2023
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6. A multimodal variational autoencoder for estimating progression scores from imaging and microRNA data in rare neurodegenerative diseases.

Author: Virgilio Kmetzsch, Emmanuelle Becker, Dario Saracino, Vincent Anquetil, Daisy Rinaldi, Agnès Camuzat, Thomas Gareau, Isabelle Le Ber, and Olivier Colliot
Published: 2022
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7. Differential early subcortical involvement in genetic FTD within the GENFI cohort

Author: Martina Bocchetta, Emily G. Todd, Georgia Peakman, David M. Cash, Rhian S. Convery, Lucy L. Russell, David L. Thomas, Juan Eugenio Iglesias, John C. van Swieten, Lize C. Jiskoot, Harro Seelaar, Barbara Borroni, Daniela Galimberti, Raquel Sanchez-Valle, Robert Laforce, Fermin Moreno, Matthis Synofzik, Caroline Graff, Mario Masellis, Maria Carmela Tartaglia, James B. Rowe, Rik Vandenberghe, Elizabeth Finger, Fabrizio Tagliavini, Alexandre de Mendonça, Isabel Santana, Chris R. Butler, Simon Ducharme, Alexander Gerhard, Adrian Danek, Johannes Levin, Markus Otto, Sandro Sorbi, Isabelle Le Ber, Florence Pasquier, Jonathan D. Rohrer, Sónia Afonso, Maria Rosario Almeida, Sarah Anderl-Straub, Christin Andersson, Anna Antonell, Silvana Archetti, Andrea Arighi, Mircea Balasa, Myriam Barandiaran, Nuria Bargalló, Robart Bartha, Benjamin Bender, Alberto Benussi, Maxime Bertoux, Anne Bertrand, Valentina Bessi, Sandra Black, Sergi Borrego-Ecija, Jose Bras, Alexis Brice, Rose Bruffaerts, Agnès Camuzat, Marta Cañada, Valentina Cantoni, Paola Caroppo, Miguel Castelo-Branco, Olivier Colliot, Thomas Cope, Vincent Deramecourt, María de Arriba, Giuseppe Di Fede, Alina Díez, Diana Duro, Chiara Fenoglio, Camilla Ferrari, Catarina B. Ferreira, Nick Fox, Morris Freedman, Giorgio Fumagalli, Aurélie Funkiewiez, Alazne Gabilondo, Roberto Gasparotti, Serge Gauthier, Stefano Gazzina, Giorgio Giaccone, Ana Gorostidi, Caroline Greaves, Rita Guerreiro, Carolin Heller, Tobias Hoegen, Begoña Indakoetxea, Vesna Jelic, Hans-Otto Karnath, Ron Keren, Gregory Kuchcinski, Tobias Langheinrich, Thibaud Lebouvier, Maria João Leitão, Albert Lladó, Gemma Lombardi, Sandra Loosli, Carolina Maruta, Simon Mead, Lieke Meeter, Gabriel Miltenberger, Rick van Minkelen, Sara Mitchell, Katrina Moore, Benedetta Nacmias, Annabel Nelson, Jennifer Nicholas, Linn Öijerstedt, Jaume Olives, Sebastien Ourselin, Alessandro Padovani, Jessica Panman, Janne M. Papma, Yolande Pijnenburg, Cristina Polito, Enrico Premi, Sara Prioni, Catharina Prix, Rosa Rademakers, Veronica Redaelli, Daisy Rinaldi, Tim Rittman, Ekaterina Rogaeva, Adeline Rollin, Pedro Rosa-Neto, Giacomina Rossi, Martin Rossor, Beatriz Santiago, Dario Saracino, Sabrina Sayah, Elio Scarpini, Sonja Schönecker, Elisa Semler, Rachelle Shafei, Christen Shoesmith, Imogen Swift, Miguel Tábuas-Pereira, Mikel Tainta, Ricardo Taipa, David Tang-Wai, Paul Thompson, Hakan Thonberg, Carolyn Timberlake, Pietro Tiraboschi, Philip Van Damme, Mathieu Vandenbulcke, Michele Veldsman, Ana Verdelho, Jorge Villanua, Jason Warren, Carlo Wilke, Ione Woollacott, Elisabeth Wlasich, Henrik Zetterberg, and Miren Zulaica
Subjects: Genetic frontotemporal dementia, MRI imaging, Brain volumetry, Presymptomatic stage, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract: Background: Studies have previously shown evidence for presymptomatic cortical atrophy in genetic FTD. Whilst initial investigations have also identified early deep grey matter volume loss, little is known about the extent of subcortical involvement, particularly within subregions, and how this differs between genetic groups. Methods: 480 mutation carriers from the Genetic FTD Initiative (GENFI) were included (198 GRN, 202 C9orf72, 80 MAPT), together with 298 non-carrier cognitively normal controls. Cortical and subcortical volumes of interest were generated using automated parcellation methods on volumetric 3 T T1-weighted MRI scans. Mutation carriers were divided into three disease stages based on their global CDR® plus NACC FTLD score: asymptomatic (0), possibly or mildly symptomatic (0.5) and fully symptomatic (1 or more). Results: In all three groups, subcortical involvement was seen at the CDR 0.5 stage prior to phenoconversion, whereas in the C9orf72 and MAPT mutation carriers there was also involvement at the CDR 0 stage. In the C9orf72 expansion carriers the earliest volume changes were in thalamic subnuclei (particularly pulvinar and lateral geniculate, 9–10%) cerebellum (lobules VIIa-Crus II and VIIIb, 2–3%), hippocampus (particularly presubiculum and CA1, 2–3%), amygdala (all subregions, 2–6%) and hypothalamus (superior tuberal region, 1%). In MAPT mutation carriers changes were seen at CDR 0 in the hippocampus (subiculum, presubiculum and tail, 3–4%) and amygdala (accessory basal and superficial nuclei, 2–4%). GRN mutation carriers showed subcortical differences at CDR 0.5 in the presubiculum of the hippocampus (8%). Conclusions: C9orf72 expansion carriers show the earliest and most widespread changes including the thalamus, basal ganglia and medial temporal lobe. By investigating individual subregions, changes can also be seen at CDR 0 in MAPT mutation carriers within the limbic system. Our results suggest that subcortical brain volumes may be used as markers of neurodegeneration even prior to the onset of prodromal symptoms.
Published: 2021
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8. Interrupted CAG expansions in ATXN2 gene expand the genetic spectrum of frontotemporal dementias

Author: Clémence Fournier, Vincent Anquetil, Agnès Camuzat, Sandrine Stirati-Buron, Véronique Sazdovitch, Laura Molina-Porcel, Sabrina Turbant, Daisy Rinaldi, Raquel Sánchez-Valle, Mathieu Barbier, Morwena Latouche, Neuro-CEB Neuropathology Network, Giovanni Stevanin, Danielle Seilhean, Alexis Brice, Charles Duyckaerts, and Isabelle Le Ber
Subjects: Frontotemporal dementia, Frontotemporal lobar degeneration, TDP-43, Ataxin 2, Amyotrophic lateral sclerosis, C9orf72, Neurology. Diseases of the nervous system, RC346-429
Published: 2018
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9. New Antibody-Free Mass Spectrometry-Based Quantification Reveals That C9ORF72 Long Protein Isoform Is Reduced in the Frontal Cortex of Hexanucleotide-Repeat Expansion Carriers

Author: Arthur Viodé, Clémence Fournier, Agnès Camuzat, François Fenaille, NeuroCEB Brain Bank, Morwena Latouche, Fanny Elahi, Isabelle Le Ber, Christophe Junot, Foudil Lamari, Vincent Anquetil, François Becher, Franck Letournel, Anne Vital, Françoise Chapon, Catherine Godfraind, Claude-Alain Maurage, Vincent Deramecourt, David Meyronnet, Nathalie Streichenberger, André Maues de Paula, Valérie Rigau, Fanny Vandenbos-Burel, Charles Duyckaerts, Danielle Seilhean, Véronique Sazdovitch, Serge Milin, Dan Christian Chiforeanu, Annie Laquerrière, and Béatrice Lannes
Subjects: frontotemporal dementia (FTD), frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), C9ORF72, TDP-43, TDP43, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Frontotemporal dementia (FTD) is a fatal neurodegenerative disease characterized by behavioral and language disorders. The main genetic cause of FTD is an intronic hexanucleotide repeat expansion (G4C2)n in the C9ORF72 gene. A loss of function of the C9ORF72 protein associated with the allele-specific reduction of C9ORF72 expression is postulated to contribute to the disease pathogenesis. To better understand the contribution of the loss of function to the disease mechanism, we need to determine precisely the level of reduction in C9ORF72 long and short isoforms in brain tissue from patients with C9ORF72 mutations. In this study, we developed a sensitive and robust mass spectrometry (MS) method for quantifying C9ORF72 isoform levels in human brain tissue without requiring antibody or affinity reagent. An optimized workflow based on surfactant-aided protein extraction and pellet digestion was established for optimal recovery of the two isoforms in brain samples. Signature peptides, common or specific to the isoforms, were targeted in brain extracts by multiplex MS through the parallel reaction monitoring mode on a Quadrupole–Orbitrap high resolution mass spectrometer. The assay was successfully validated and subsequently applied to frontal cortex brain samples from a cohort of FTD patients with C9ORF72 mutations and neurologically normal controls without mutations. We showed that the C9ORF72 short isoform in the frontal cortices is below detection threshold in all tested individuals and the C9ORF72 long isoform is significantly decreased in C9ORF72 mutation carriers.
Published: 2018
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10. 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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11. Highlight on Computing disease progression scores using multimodal variational autoencoders trained with neuroimaging and microRNA data

Author: Virgilio Kmetzsch, Emmanuelle Becker, Dario Saracino, Vincent Anquetil, Daisy Rinaldi, Agnès Camuzat, Thomas Gareau, Isabelle Le Ber, Olivier Colliot, Dynamics, Logics and Inference for biological Systems and Sequences (Dyliss), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), 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), Sorbonne Université (SU), and ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019)
Subjects: [INFO.INFO-LG]Computer Science [cs]/Machine Learning [cs.LG], [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: International audience
Published: 2022

12. 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

13. Primary Progressive Aphasia Associated With GRN Mutations: New Insights Into the Nonamyloid Logopenic Variant

Author: Bruno Dubois, Audrey Gabelle, François Sellal, Jérémie Pariente, Marie Sarazin, Agnès Camuzat, Raffaella Migliaccio, Frédérique Etcharry-Bouyx, Amandine Geraudie, Sophie Ferrieux, Simona Bottani, Carole Roué-Jagot, Mira Didic, Florence Pasquier, Leila Sellami, Alexis Brice, Olivier Colliot, Fabienne Clot, Marc Teichmann, Didier Hannequin, Christel Thauvin-Robinet, Claire Boutoleau-Bretonnière, Julien Lagarde, Cinzia Coppola, David Wallon, Richard Levy, Marie Noguès-Lassiaille, Dario Saracino, Aurélie Funkiewiez, Maria Luisa Gorno-Tempini, Olivier Martinaud, Isabelle Le Ber, Marion Houot, Stéphane Epelbaum, Sophie Auriacombe, Alexandre Morin, Vincent Deramecourt, Ftd-Als, Philippe Couratier, Daisy Rinaldi, Saracino, Dario, Ferrieux, Sophie, Noguès-Lassiaille, Marie, Houot, Marion, Funkiewiez, Aurélie, Sellami, Leila, Deramecourt, Vincent, Pasquier, Florence, Couratier, Philippe, Pariente, Jérémie, Géraudie, Amandine, Epelbaum, Stéphane, Wallon, David, Hannequin, Didier, Martinaud, Olivier, Clot, Fabienne, Camuzat, Agnè, Bottani, Simona, Rinaldi, Daisy, Auriacombe, Sophie, Sarazin, Marie, Didic, Mira, Boutoleau-Bretonnière, Claire, Thauvin-Robinet, Christel, Lagarde, Julien, Roué-Jagot, Carole, Sellal, Françoi, Gabelle, Audrey, Etcharry-Bouyx, Frédérique, Morin, Alexandre, Coppola, Cinzia, Levy, Richard, Dubois, Bruno, Brice, Alexi, Colliot, Olivier, Luisa Gorno-Tempini, Maria, Teichmann, Marc, Migliaccio, Raffaella, Le Ber, Isabelle, 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), CHU Lille, CHU Limoges, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), 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)-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)-Centre National de la Recherche Scientifique (CNRS), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropsychologie et imagerie de la mémoire humaine (NIMH), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Charles Foix [AP-HP], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), GHU AP-HP Centre Université de Paris, Hôpitaux Civils de Colmar, Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), University of the Study of Campania Luigi Vanvitelli, University of California [San Francisco] (UC San Francisco), University of California (UC), The research leading to these results received funding from the Investissements davenir ANR-11-INBS-0011. This work was funded by the Programme Hospitalier de Recherche Clinique (PHRC) FTLD-exome (to ILB, promotion by Assistance Publique Hôpitaux de Paris), PHRC Predict-PGRN (to ILB, promotion by Assistance Publique Hôpitaux de Paris)., ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Admin, Oskar, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of California [San Francisco] (UCSF), University of California, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Normandie Université (NU)-Normandie Université (NU)-École Pratique des Hautes Études (EPHE)
Subjects: Oncology, medicine.medical_specialty, Apraxia, 050105 experimental psychology, Primary progressive aphasia, 03 medical and health sciences, Dementia aphasia, 0302 clinical medicine, Atrophy, Gyrus, Aphasia, Agrammatism, Internal medicine, medicine, 0501 psychology and cognitive sciences, Prospective cohort study, business.industry, 05 social sciences, respiratory system, medicine.disease, medicine.anatomical_structure, [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, Frontotemporal dementia
Abstract: ObjectiveTo determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with GRN (progranulin) mutations and to study their neuroanatomic correlates.MethodsPatients with PPA carrying GRN mutations (PPA-GRN) were selected among a national prospective research cohort of 1,696 patients with frontotemporal dementia, including 235 patients with PPA. All patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and gray matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls and patients with sporadic PPA.ResultsAmong the 235 patients with PPA, 45 (19%) carried GRN mutations, and we studied 32 of these. We showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (n = 13, 41%), followed by nonfluent/agrammatic (nfvPPA; n = 9, 28%) and mixed forms (n = 8, 25%). Semantic variant was rather rare (n = 2, 6%). Patients with lvPPA, qualified as nonamyloid lvPPA, presented canonical logopenic deficit. Seven of 13 had a pure form; 6 showed subtle additional linguistic deficits not fitting criteria for mixed PPA and hence were labeled as logopenic-spectrum variant. GM atrophy involved primarily left posterior temporal gyrus, mirroring neuroanatomic changes of amyloid-positive-lvPPA. Patients with nfvPPA presented agrammatism (89%) rather than apraxia of speech (11%).ConclusionsThis study shows that the most frequent PPA variant associated with GRN mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. GRN testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming GRN gene–specific therapies.
Published: 2021
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14. Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications

Author: Fabienne Clot, Florence Pasquier, Didier Hannequin, Olivier Colliot, Armelle Rametti-Lacroux, Sophie Auriacombe, Raffaella Migliaccio, Ludmila Jornea, Marion Houot, Agnès Camuzat, Carole Azuar, Alexis Brice, Mathilde Sauvée, Philippe Martin-Hardy, Richard Levy, Philippe Couratier, Isabelle Le Ber, Jérémie Pariente, Claire Boutoleau-Bretonnière, Karim Dorgham, Dario Saracino, Bruno Dubois, Mira Didic, Daisy Rinaldi, Prev-Demals, David Wallon, Predict-PGRN study groups, Ftd-Als, Sylvie Forlani, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Lille 2 - Faculté de Médecine, CHU Limoges, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU), CIC - Nantes, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Institut de Neurosciences des Systèmes (INS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Hôpital de la Timone [CHU - APHM] (TIMONE), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), The research leading to these results received funding from the ’Investissements d’avenir’ ANR-11- INBS-0011. This work was partially funded by the Programme Hospitalier de Recherche Clinique (PHRC) Predict- PGRN (to ILB, promotion by Assistance Publique–Hôpitaux de Paris), the PHRC FTLD- exome (to ILB, promotion by Assistance Publique–Hôpitaux de Paris), by the ANR- PRTS PREV- DEMALS project (to ILB, grant number ANR-14- CE15-0016-07, promotion by Assistance Publique–Hôpitaux de Paris) and the Fondation Vaincre Alzheimer (to ILB, grant number FR-17035)., ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), 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), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Faculté de Médecine Henri Warembourg - Université de Lille, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Saracino, Dario, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées
Subjects: Oncology, 0303 health sciences, medicine.medical_specialty, business.industry, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Disease progression, Youden's J statistic, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, Therapeutic trial, 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, C9orf72, Internal medicine, Medicine, Biomarker (medicine), Surgery, Neurology (clinical), Amyotrophic lateral sclerosis, business, Trial registration, 030217 neurology & neurosurgery, 030304 developmental biology, Frontotemporal dementia
Abstract: ObjectiveNeurofilament 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.MethodsWe 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.ResultspNfL levels increased with age in controls, from ~5 to~18 pg/mL (pGRN patients had higher levels than C9orf72 (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72 patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades.ConclusionsThis study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression.Trial registration numbersNCT02590276 and NCT04014673.
Published: 2021
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15. Plasma microRNA signature in presymptomatic and symptomatic subjects with C9orf72 -associated frontotemporal dementia and amyotrophic lateral sclerosis

Author: Noémie Robil, Agnès Camuzat, Vincent Anquetil, Isabelle Le Ber, Ivan Moszer, Florence Pasquier, Philippe Couratier, Emmanuelle Becker, Ludmila Jornea, David Wallon, Olivier Colliot, Dario Saracino, Sylvie Forlani, Thomas Gareau, Daisy Rinaldi, Virgilio Kmetzsch, Pierre de la Grange, Dynamics, Logics and Inference for biological Systems and Sequences (Dyliss), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes 1 (UR1), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), 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), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), Service de Neurologie [CHU Limoges], CHU Limoges, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Rouen, Université de Lille, Département de neurologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), GenoSplice [Paris], FRONTLAB: Fonctions et dysfonctions de systèmes frontaux [ICM Paris] (FRONTlab), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), ANR-14-CE15-0016,PREV-DEMALS,Prédire pour prévenir les démences frontotemporales (DFT) et la sclérose latérale amyotrophique (SLA)(2014), ANR-11-INBS-0013,IFB (ex Renabi-IFB),Institut français de bioinformatique(2011), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École pratique des hautes études (EPHE), Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), FRONTlab - Systèmes frontaux : fonctions et dysfonctions (FRONTlab), Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Kmetzsch, Virgilio, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, Appel à projets générique - Prédire pour prévenir les démences frontotemporales (DFT) et la sclérose latérale amyotrophique (SLA) - - PREV-DEMALS2014 - ANR-14-CE15-0016 - Appel à projets générique - VALID, Infrastructures - Institut français de bioinformatique - - IFB (ex Renabi-IFB)2011 - ANR-11-INBS-0013 - INBS - VALID, Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Oncology, medicine.medical_specialty, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Chromosome 9, Disease, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, [STAT.ML]Statistics [stat]/Machine Learning [stat.ML], C9orf72, Internal medicine, microRNA, medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Amyotrophic lateral sclerosis, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Mutation, business.industry, medicine.disease, [STAT.ML] Statistics [stat]/Machine Learning [stat.ML], Psychiatry and Mental health, Surgery, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract: ObjectiveTo identify potential biomarkers of preclinical and clinical progression in chromosome 9 open reading frame 72 gene (C9orf72)-associated disease by assessing the expression levels of plasma microRNAs (miRNAs) in C9orf72 patients and presymptomatic carriers.MethodsThe PREV-DEMALS study is a prospective study including 22 C9orf72 patients, 45 presymptomatic C9orf72 mutation carriers and 43 controls. We assessed the expression levels of 2576 miRNAs, among which 589 were above noise level, in plasma samples of all participants using RNA sequencing. The expression levels of the differentially expressed miRNAs between patients, presymptomatic carriers and controls were further used to build logistic regression classifiers.ResultsFour miRNAs were differentially expressed between patients and controls: miR-34a-5p and miR-345-5p were overexpressed, while miR-200c-3p and miR-10a-3p were underexpressed in patients. MiR-34a-5p was also overexpressed in presymptomatic carriers compared with healthy controls, suggesting that miR-34a-5p expression is deregulated in cases with C9orf72 mutation. Moreover, miR-345-5p was also overexpressed in patients compared with presymptomatic carriers, which supports the correlation of miR-345-5p expression with the progression of C9orf72-associated disease. Together, miR-200c-3p and miR-10a-3p underexpression might be associated with full-blown disease. Four presymptomatic subjects in transitional/prodromal stage, close to the disease conversion, exhibited a stronger similarity with the expression levels of patients.ConclusionsWe identified a signature of four miRNAs differentially expressed in plasma between clinical conditions that have potential to represent progression biomarkers for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. This study suggests that dysregulation of miRNAs is dynamically altered throughout neurodegenerative diseases progression, and can be detectable even long before clinical onset.Trial registration numberNCT02590276.
Published: 2020
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16. Primary Progressive Aphasia Associated With

Author: Dario, Saracino, Sophie, Ferrieux, Marie, Noguès-Lassiaille, Marion, Houot, Aurélie, Funkiewiez, Leila, Sellami, Vincent, Deramecourt, Florence, Pasquier, Philippe, Couratier, Jérémie, Pariente, Amandine, Géraudie, Stéphane, Epelbaum, David, Wallon, Didier, Hannequin, Olivier, Martinaud, Fabienne, Clot, Agnès, Camuzat, Simona, Bottani, Daisy, Rinaldi, Sophie, Auriacombe, Marie, Sarazin, Mira, Didic, Claire, Boutoleau-Bretonnière, Christel, Thauvin-Robinet, Julien, Lagarde, Carole, Roué-Jagot, François, Sellal, Audrey, Gabelle, Frédérique, Etcharry-Bouyx, Alexandre, Morin, Cinzia, Coppola, Richard, Levy, Bruno, Dubois, Alexis, Brice, Olivier, Colliot, Maria Luisa, Gorno-Tempini, Marc, Teichmann, Raffaella, Migliaccio, Isabelle, Le Ber, and Martine, Vercelletto
Subjects: Male, Tomography, Emission-Computed, Single-Photon, Language Tests, Middle Aged, Neuropsychological Tests, Magnetic Resonance Imaging, Cohort Studies, Aphasia, Primary Progressive, Cross-Sectional Studies, Progranulins, Gene Frequency, Frontotemporal Dementia, Mutation, Humans, Speech, Female, Prospective Studies, Atrophy, Biomarkers, Aged
Abstract: To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated withPatients with PPA carryingAmong the 235 patients with PPA, 45 (19%) carriedThis study shows that the most frequent PPA variant associated with
Published: 2020

17. Plasma microRNA signature in presymptomatic and symptomatic subjects with

Author: Virgilio, Kmetzsch, Vincent, Anquetil, Dario, Saracino, Daisy, Rinaldi, Agnès, Camuzat, Thomas, Gareau, Ludmila, Jornea, Sylvie, Forlani, Philippe, Couratier, David, Wallon, Florence, Pasquier, Noémie, Robil, Pierre, de la Grange, Ivan, Moszer, Isabelle, Le Ber, Olivier, Colliot, and Emmanuelle, Becker
Subjects: Adult, Male, C9orf72 Protein, Amyotrophic Lateral Sclerosis, Middle Aged, MicroRNAs, Frontotemporal Dementia, Mutation, Exome Sequencing, Disease Progression, Humans, Female, Biomarkers, Aged
Abstract: To identify potential biomarkers of preclinical and clinical progression in chromosome 9 open reading frame 72 gene (The PREV-DEMALS study is a prospective study including 22Four miRNAs were differentially expressed between patients and controls: miR-34a-5p and miR-345-5p were overexpressed, while miR-200c-3p and miR-10a-3p were underexpressed in patients. MiR-34a-5p was also overexpressed in presymptomatic carriers compared with healthy controls, suggesting that miR-34a-5p expression is deregulated in cases withWe identified a signature of four miRNAs differentially expressed in plasma between clinical conditions that have potential to represent progression biomarkers forNCT02590276.
Published: 2020

18. Plasma progranulin levels for frontotemporal dementia in clinical practice: a 10-year French experience

Author: Leila, Sellami, Benoît, Rucheton, Imen, Ben Younes, Agnès, Camuzat, Dario, Saracino, Daisy, Rinaldi, Stephane, Epelbaum, Carole, Azuar, Richard, Levy, Sophie, Auriacombe, Didier, Hannequin, Jérémie, Pariente, Mathieu, Barbier, Claire, Boutoleau-Bretonnière, Philippe, Couratier, Florence, Pasquier, Vincent, Deramecourt, Mathilde, Sauvée, Marie, Sarazin, Julien, Lagarde, Carole, Roué-Jagot, Sylvie, Forlani, Ludmila, Jornea, Isabelle, David, Eric, LeGuern, Bruno, Dubois, Alexis, Brice, Fabienne, Clot, Foudil, Lamari, Isabelle, Le Ber, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], 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), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Bordeaux [Bordeaux], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Services de Neurologie [CHU Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], 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, Neuroendocrinologie et physiopathologie neuronale, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Pôle Psychiatrie et Neurologie [Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), and Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]
Subjects: Adult, Male, Heterozygote, Sex Characteristics, Time Factors, Progranulin (GRN), Plasma progranulin levels, Middle Aged, SEPIA, Progranulins, Predictive Value of Tests, Mutation, C9orf72, Humans, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, Age of Onset, Frontotemporal Lobar Degeneration, Biomarkers, Frontotemporal dementia, Aged
Abstract: International audience; GRN mutations are frequent causes of familial frontotemporal degeneration. Although there is no clear consensual threshold, plasma progranulin levels represent an efficient biomarker for predicting GRN mutations when decreased. We evaluated plasma levels to determine whether it could also predict age at onset, clinical phenotype, or disease progression in 160 GRN carriers. Importantly, progranulin levels were influenced by gender, with lower levels in male than in female patients in our study. Although we found no correlation with age at onset or with clinical phenotype, we confirmed that decreased level predicts GRN mutations, even in presymptomatic carriers more than four decades before disease onset. We also provided first evidence for the stability of levels throughout longitudinal trajectory in carriers, over a 4-year time span. Finally, we confirmed that progranulin levels constitute a reliable, cost-effective marker, suitable as a screening tool in patients with familial frontotemporal degeneration, and more broadly in patients without family history or with atypical presentations who are less likely to be referred for molecular diagnosis.
Published: 2020
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19. The missense p.Trp7Arg mutation in GRN gene leads to progranulin haploinsufficiency

Author: Imen Benyounes, Julien Lagarde, Benoit Rucheton, Leila Sellami, Alexis Brice, Fabienne Clot, Sylvie Forlani, Eric LeGuern, Carole Roué-Jagot, Ludmila Jornea, Dario Saracino, Agnès Camuzat, Bruno Dubois, Marie Sarazin, Foudil Lamari, Isabelle Le Ber, 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), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagerie Moléculaire in Vivo (IMIV - U1023 - ERL9218), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), GHU Paris Psychiatrie et Neurosciences, École pratique des hautes études (EPHE), CCSD, Accord Elsevier, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Signal peptide, Aging, Progranulin, TDP-43, Genetic counseling, [SDV]Life Sciences [q-bio], Mutation, Missense, Haploinsufficiency, Biology, medicine.disease_cause, Frontotemporal lobar degeneration, 03 medical and health sciences, Progranulins, 0302 clinical medicine, C9orf72, mental disorders, medicine, Humans, Missense mutation, Genetics, Mutation, C9orf72 Protein, General Neuroscience, Middle Aged, medicine.disease, 3. Good health, DNA-Binding Proteins, [SDV] Life Sciences [q-bio], 030104 developmental biology, Female, Neurology (clinical), Geriatrics and Gerontology, 030217 neurology & neurosurgery, Frontotemporal dementia, GRN, Developmental Biology
Abstract: International audience; GRN null mutations are among the main genetic causes of frontotemporal dementia through progranulin haploinsufficiency. Most missense mutations are considered not pathogenic. The p.Trp7Arg substitution is localized within the signal peptide domain and no formal evidence for its pathogenicity has yet been provided. We identified the p.Trp7Arg substitution in 3 carriers with low plasma progranulin levels. This evidences that this missense mutation leads to functional haploinsufficiency and should thus be considered pathogenic. Assessing the pathogenicity of variants of unknown significance has significant implications for clinical practice, genetic counseling, and future therapeutic interventions.
Published: 2020
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20. Cognitive inhibition impairments in presymptomatic

Author: Maxime, Montembeault, Sabrina, Sayah, Daisy, Rinaldi, Benjamin, Le Toullec, Anne, Bertrand, Aurélie, Funkiewiez, Dario, Saracino, Agnès, Camuzat, Philippe, Couratier, Marianne, Chouly, Didier, Hannequin, Carole, Aubier-Girard, Florence, Pasquier, Xavier, Delbeuck, Olivier, Colliot, Bénédicte, Batrancourt, Carole, Azuar, Richard, Lévy, Bruno, Dubois, Isabelle, Le Ber, Raffaella, Migliaccio, and David, Wallon
Subjects: Adult, Male, Heterozygote, Inhibition, Psychological, C9orf72 Protein, Brain, Humans, Cognitive Dysfunction, Female, Middle Aged, Neuropsychological Tests
Abstract: To investigate cognitive inhibition in presymptomaticThirty-eight presymptomaticC9+ individuals younger than 40 years had higher error scores (part B) but equivalent HSCT time to completion (part B-part A) compared to C9- individuals. C9+ individuals older than 40 years had both higher error scores and longer time to completion. HSCT time to completion significantly predicted the proximity to estimated clinical conversion from presymptomatic to symptomatic phase in C9+ individuals (based on the average age at onset of affected relatives in the family). Anatomically, we found that HSCT time to completion was associated with the integrity of the cerebellum.The HSCT represents a good marker of cognitive inhibition impairments in C9+ and of proximity to clinical conversion. This study also highlights the key role of the cerebellum in cognitive inhibition.
Published: 2019

21. Presymptomatic spinal cord pathology in c9orf72 mutation carriers: a longitudinal neuroimaging study

Author: Olivier Colliot, Dario Saracino, Isabelle Le Ber, Agnès Camuzat, Mélanie Pélégrini-Issac, Véronique Marchand-Pauvert, Menghan Li, Daisy Rinaldi, François Salachas, Peter Bede, Mohamed-Mounir El Mendili, Giorgia Querin, Julien Cohen-Adad, Martin Catala, Pierre-François Pradat, 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), 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), Fédération des Maladies du Système Nerveux, 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), École Polytechnique de Montréal (EPM), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), 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)-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)-Centre National de la Recherche Scientifique (CNRS), This study was supported by the Assistance Publique – Hôpitaux de Paris (Clinical Research and Development Department) grant ANR/DGOS PRTS 2015 -2019 PrevDemAls (to I.L.B.), the 'Investissements d’avenir' ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-Investissements-Avenir Institut-Hospitalo-Universitaire-06), the Centre d’Investigation Clinique (CIC 1422), and the Centre pour l’Acquisition et le Traitement des Images (CATI) platform, at IHU-A-ICM, Paris, France. Peter Bede is supported by the Health Research Board (HRB EIA-2017-019), the Andrew Lydon scholarship, the Irish Institute of Clinical Neuroscience IICN − Novartis Ireland Research Grant, and the Iris O'Brien Foundation., ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Colliot, Olivier, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Pathology, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, 0302 clinical medicine, [INFO.INFO-CV] Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Longitudinal Studies, Prospective Studies, Amyotrophic lateral sclerosis, medicine.diagnostic_test, Middle Aged, 3. Good health, medicine.anatomical_structure, Neurology, Spinal Cord, [INFO.INFO-TI] Computer Science [cs]/Image Processing [eess.IV], Frontotemporal Dementia, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], medicine.symptom, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Frontotemporal dementia, Adult, medicine.medical_specialty, Heterozygote, Neuroimaging, Asymptomatic, 03 medical and health sciences, Young Adult, Atrophy, Fractional anisotropy, medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, Aged, [SPI.SIGNAL] Engineering Sciences [physics]/Signal and Image processing, C9orf72 Protein, business.industry, Amyotrophic Lateral Sclerosis, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Magnetic resonance imaging, medicine.disease, Spinal cord, 030104 developmental biology, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Corticospinal tract, Asymptomatic Diseases, Mutation, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: International audience; OBJECTIVE:C9orf72 hexanucleotide repeats expansions account for almost half of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases. Recent imaging studies in asymptomatic C9orf72 carriers have demonstrated cerebral white (WM) and gray matter (GM) degeneration before the age of 40 years. The objective of this study was to characterize cervical spinal cord (SC) changes in asymptomatic C9orf72 hexanucleotide carriers.METHODS:Seventy-two asymptomatic individuals were enrolled in a prospective study of first-degree relatives of ALS and FTD patients carrying the c9orf72 hexanucleotide expansion. Forty of them carried the pathogenic mutation (C9+ ). Each subject underwent quantitative cervical cord imaging. Structural GM and WM metrics and diffusivity parameters were evaluated at baseline and 18 months later. Data were analyzed in C9+ and C9- subgroups, and C9+ subjects were further stratified by age.RESULTS:At baseline, significant WM atrophy was detected at each cervical vertebral level in C9+ subjects older than 40 years without associated changes in GM and diffusion tensor imaging parameters. At 18-month follow-up, WM atrophy was accompanied by significant corticospinal tract (CST) fractional anisotropy (FA) reductions. Intriguingly, asymptomatic C9+ subjects older than 40 years with family history of ALS (as opposed to FTD) also exhibited significant CST FA reduction at baseline.INTERPRETATION:Cervical SC imaging detects WM atrophy exclusively in C9+ subjects older than 40 years, and progressive CST FA reductions can be identified on 18-month follow-up. Cervical SC magnetic resonance imaging readily captures presymptomatic pathological changes and disease propagation in c9orf72-associated conditions. ANN NEUROL 2019;86:158-167.
Published: 2019
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22. Homozygous GRN mutations: unexpected phenotypes and new insights into pathological and molecular mechanisms: New insights in homozygous GRN mutations

Author: Antoinette Gelot, Alexis Brice, Agnès Camuzat, Benoit Rucheton, Laureen Chat, Dario Saracino, Frédérique Fluchère, Johannes Alexander Lobrinus, Fabienne Clot, Sylvie Forlani, Peter Myers, Alexandra Durr, Ludmila Jornea, Isabelle Le Ber, Vincent Huin, Foudil Lamari, Mathieu Barbier, Armand Bottani, Catherine Caillaud, Stéphane Auvin, Charles Duyckaerts, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Technocentre Renault [Guyancourt], RENAULT, Génétique médicale, Hôpitaux Universitaires de Genève (HUG), University of Geneva [Switzerland], Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Université de Bordeaux (UB), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie pédiatrique et maladies métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Polytech'Paris-UPMC, Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Geneva University Hospital (HUG), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université de Paris (UP), Medical Office [Geneva, Switzerland], Service de pathologie [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neuropathologie [CHU Pitié Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Cité (UPCité), Sorbonne Université, Institut du Cerveau et de la Moelle épinière (ICM), AP-HP, INSERM, CNRS, University Hospital Pitié - Salpêtrière, Paris, France, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP]
Subjects: Male, MESH: Epilepsy / genetics, MESH: Neuronal Ceroid-Lipofuscinoses / diagnostic imaging, MESH: TDP-43 Proteinopathies / physiopathology, MESH: RNA Splicing / genetics, ddc:616.07, 0302 clinical medicine, MESH: Child, MESH: Cerebellar Ataxia / genetics, ddc:576.5, Age of Onset, Child, ComputingMilieux_MISCELLANEOUS, Mutation, MESH: Middle Aged, 3. Good health, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Neuronal ceroid lipofuscinosis, MESH: Parkinsonian Disorders / genetics, MESH: Cognitive Dysfunction / genetics, MESH: Young Adult, Frontotemporal Dementia, GRN, Retinitis Pigmentosa, MESH: Progranulins / metabolism, MESH: Rare Diseases, MESH: Frontotemporal Dementia / genetics, Cerebellar Ataxia, MESH: Age of Onset, RNA Splicing, 03 medical and health sciences, Parkinsonian Disorders, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Retinitis pigmentosa, Humans, Cognitive Dysfunction, MESH: Adolescent, MESH: Humans, Epilepsy, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: TDP-43 Proteinopathies / diagnostic imaging, 030104 developmental biology, FOS: Biological sciences, Neurology (clinical), MESH: Frontotemporal Dementia / physiopathology, MESH: Female, 030217 neurology & neurosurgery, 0301 basic medicine, TDP-43, medicine.disease_cause, Progranulins, MESH: Heterozygote, Genetics, Homozygote, Frontotemporal lobar degeneration, Middle Aged, MESH: Neuronal Ceroid-Lipofuscinoses / physiopathology, frontotemporal lobar degeneration, Neurons and Cognition (q-bio.NC), MESH: Parkinsonian Disorders / diagnostic imaging, MESH: TDP-43 Proteinopathies / genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, medicine.symptom, MESH: Neuronal Ceroid-Lipofuscinoses / genetics, Frontotemporal dementia, MESH: Homozygote, Adult, Progranulin, Heterozygote, MESH: Mutation, Adolescent, MESH: Parkinsonian Disorders / physiopathology, Biology, MESH: Frontotemporal Dementia / diagnostic imaging, Young Adult, Rare Diseases, Neuronal Ceroid-Lipofuscinoses, MESH: Retinitis Pigmentosa / genetics, medicine, Dementia, Quantitative Biology - Genomics, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Genomics (q-bio.GN), Cerebellar ataxia, MESH: Progranulins / genetics, Biomolecules (q-bio.BM), MESH: Male, Quantitative Biology - Biomolecules, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Quantitative Biology - Neurons and Cognition, TDP-43 Proteinopathies, Age of onset, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Homozygous mutations in the progranulin gene (GRN) are associated with neuronal ceroid lipofuscinosis 11 (CLN11), a rare lysosomal-storage disorder characterized by cerebellar ataxia, seizures, retinitis pigmentosa, and cognitive disorders, usually beginning between 13 and 25 years of age. This is a rare condition, previously reported in only four families. In contrast, heterozygous GRN mutations are a major cause of frontotemporal dementia associated with neuronal cytoplasmic TDP-43 inclusions. We identified homozygous GRN mutations in six new patients. The phenotypic spectrum is much broader than previously reported, with two remarkably distinct presentations, depending on the age of onset. A childhood/juvenile form is characterized by classical CLN11 symptoms at an early age at onset. Unexpectedly, other homozygous patients presented a distinct delayed phenotype of frontotemporal dementia and parkinsonism after 50 years; none had epilepsy or cerebellar ataxia. Another major finding of this study is that all GRN mutations may not have the same impact on progranulin protein synthesis. A hypomorphic effect of some mutations is supported by the presence of residual levels of plasma progranulin and low levels of normal transcript detected in one case with a homozygous splice-site mutation and late onset frontotemporal dementia. This is a new critical finding that must be considered in therapeutic trials based on replacement strategies. The first neuropathological study in a homozygous carrier provides new insights into the pathological mechanisms of the disease. Hallmarks of neuronal ceroid lipofuscinosis were present. The absence of TDP-43 cytoplasmic inclusions markedly differs from observations of heterozygous mutations, suggesting a pathological shift between lysosomal and TDP-43 pathologies depending on the mono or bi-allelic status. An intriguing observation was the loss of normal TDP-43 staining in the nucleus of some neurons, which could be the first stage of the TDP-43 pathological process preceding the formation of typical cytoplasmic inclusions. Finally, this study has important implications for genetic counselling and molecular diagnosis. Semi-dominant inheritance of GRN mutations implies that specific genetic counselling should be delivered to children and parents of CLN11 patients, as they are heterozygous carriers with a high risk of developing dementia. More broadly, this study illustrates the fact that genetic variants can lead to different phenotypes according to their mono- or bi-allelic state, which is a challenge for genetic diagnosis.
Published: 2019
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23. Les neurofilaments plasmatiques comme biomarqueurs pour le suivi longitudinal des porteurs de mutations de GRN et C9orf72

Author: Isabelle Le Ber, Karim Dorgham, Agnès Camuzat, Dario Saracino, Marion Houot, and Fabienne Clot
Subjects: Neurology, Neurology (clinical)
Abstract: Introduction A l’approche de therapies ciblees dans les formes genetiques de demence frontotemporale (DFT) et sclerose laterale amyotrophique (SLA), l’identification des biomarqueurs d’evolution presymptomatique et conversion clinique represente un enjeu majeur. Objectifs Nous souhaitions evaluer les niveaux plasmatiques de la chaine legere des neurofilaments (NfL) afin d’en determiner les principaux facteurs de variabilite et leur potentiel comme marqueur d’evolution de la maladie. Patients et methodes Au total, 358 sujets ont ete inclus dans les protocoles PREV-DEMALS, Predict-PGRN, ou par le reseau national sur la DFT/DFT-SLA. La population comportait 101 patients (53 porteurs d’expansion C9orf72, 48 de mutation GRN), 87 porteurs presymptomatiques (49 C9orf72, 38 GRN) et 170 controles. Les participants avaient eu entre 1 a 6 prelevements plasmatiques pendant un suivi moyen de 4 ans. Le dosage des NfL a ete effectue avec la technique ELISA ultrasensible SIngle MOlecule Array (SIMOA). Resultats Les valeurs de NfL etaient plus elevees chez les patients comparees aux controles et presymptomatiques, sans impact du sexe. Les valeurs des controles correlaient avec l’âge au prelevement, et le taux d’augmentation annualise moyen etait 3,9 %. Le genotype avait un impact chez les patients, avec des valeurs de base et une progression plus importantes associees aux mutations GRN. Les NfL chez les presymptomatiques, comparables aux controles a l’inclusion, augmentaient significativement dans un sous-groupe. Discussion Le dosage plasmatique des NfL avec la technique SIMOA s’avere un marqueur utile pour tracer l’evolution de maladie chez les porteurs des mutations GRN et C9orf72, les principales causes genetiques de DFT et/ou SLA. Un suivi longitudinal approprie chez les porteurs presymptomatiques pourrait permettre de monitorer leur phase preclinique et d’identifier ceux proches de la phenoconversion. Conclusion Cette etude confirme la relation entre NfL et processus degeneratif dans le contexte des mutations GRN et C9orf72, et propose des seuils pathologiques adaptes en fonction de l’âge au prelevement.
Published: 2021
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24. Novel VCP mutations expand the mutational spectrum of frontotemporal dementia

Author: Didier Hannequin, Agnès Camuzat, Yassaman Ghassab, Isabelle David, Sylvie Forlani, Morwena Latouche, Dario Saracino, Eric Le Guern, Lena Guillot-Noel, Cinzia Coppola, Mira Didic, Daisy Rinaldi, Vincent Anquetil, Lucie Guyant-Maréchal, Alexis Brice, Ftd-Als, Fabienne Clot, Giuseppe Di Iorio, Isabelle Le Ber, 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), Second Division of Neurology, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania 'Luigi Vanvitelli', Naples, Italy, 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), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Otten, Lisa, Saracino, Dario, Clot, Fabienne, Camuzat, Agnè, Anquetil, Vincent, Hannequin, Didier, Guyant-Maréchal, Lucie, Didic, Mira, Guillot-Noël, Léna, Rinaldi, Daisy, Latouche, Morwena, Forlani, Sylvie, Ghassab, Yassaman, Coppola, Cinzia, Di Iorio, Giuseppe, David, Isabelle, Le Guern, Eric, Brice, Alexi, Le Ber, Isabelle, CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Male, Aging, Valosin-containing protein, Mutation, Missense, Frontotemporal lobar degeneration, medicine.disease_cause, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Valosin Containing Protein, medicine, Dementia, Humans, Amyotrophic lateral sclerosis, Gene, Amyotrophic lateral sclerosi, ComputingMilieux_MISCELLANEOUS, Aged, Genetics, Mutation, biology, [SCCO.NEUR]Cognitive science/Neuroscience, General Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, TAR DNA binding protein 43, Middle Aged, medicine.disease, Pedigree, 030104 developmental biology, Paget's disease of bone, Frontotemporal Dementia, biology.protein, Neurology (clinical), Geriatrics and Gerontology, 030217 neurology & neurosurgery, Developmental Biology, Frontotemporal dementia
Abstract: Valosin-containing protein (VCP) mutations are rare causes of autosomal dominant frontotemporal dementias associated with Paget's disease of bone, inclusion body myopathy, and amyotrophic lateral sclerosis. We analyzed the VCP gene in a cohort of 199 patients with frontotemporal dementia and identified 7 heterozygous mutations in unrelated families, including 3 novel mutations segregating with dementia. This expands the VCP mutation spectrum and suggests that although VCP mutations are rare (3.5% in this study), the gene should be analyzed even in absence of the full syndromic complex. Reporting genetic variants with convincing arguments for pathogenicity is important considering the large amount of data generated by next-generation sequencing and the growing difficulties to interpret rare genetic variants identified in isolated cases.
Published: 2018
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25. Factors influencing the age at onset in familial frontotemporal lobar dementia: Important weight of genetics

Author: Kathy Larcher, Florence Pasquier, Emmanuelle Génin, Marion Houot, Alexis Brice, Jérémie Pariente, Didier Hannequin, Paola Caroppo, Agnès Camuzat, Clémence Fournier, Audrey Sabbagh, Isabelle Le Ber, Fabienne Clot, Daisy Rinaldi, and Mathieu Barbier
Subjects: 0301 basic medicine, Genetics, Genetic counseling, Heritability, Biology, medicine.disease, Explained variation, Article, Correlation, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, C9orf72, medicine, Dementia, Variance components, Neurology (clinical), Amyotrophic lateral sclerosis, 030217 neurology & neurosurgery, Genetics (clinical)
Abstract: Objective:To quantify the effect of genetic factors and generations influencing the age at onset (AAO) in families with frontotemporal lobar dementia (FTD) due to C9ORF72 hexanucleotide repeat expansions and GRN mutations.Methods:We studied 504 affected individuals from 133 families with C9ORF72 repeat expansions and 90 FTD families with mutations in GRN, 2 major genes responsible for FTD and/or amyotrophic lateral sclerosis. Intrafamilial correlations of AAO were analyzed, and variance component methods were used for heritability estimates. Generational effects on hazard rates for AAO were assessed using mixed-effects Cox proportional hazard models.Results:A generational effect influencing AAO was detected in both C9ORF72 and GRN families. Nevertheless, the estimated proportion of AAO variance explained by genetic factors was high in FTD caused by C9ORF72 repeat expansions (44%; p = 1.10e−4), 62% when the AAO of dementia was specifically taken into account (p = 8.10e−5), and to a lesser degree in GRN families (26%; p = 0.17). Intrafamilial correlation analyses revealed a significant level of correlations in C9ORF72 families according to the degree of kinship. A pattern of intrafamilial correlations also suggested potential X-linked modifiers acting on AAO. Nonsignificant correlation values were observed in GRN families.Conclusions:Our results provide original evidence that genetic modifiers strongly influence the AAO in C9ORF72 carriers, while their effects seem to be weaker in GRN families. This constitutes a rational to search for genetic biomarkers, which could help to improve genetic counseling, patient care, and monitoring of therapeutic trials.
Published: 2017

26. [P3–364]: ACCELERATED SUBCORTICAL ATROPHY DURING AGING IN PRESYMPTOMATIC CARRIERS OF C9ORF72 MUTATION

Author: Florence Pasquier, Agnès Camuzat, Anne Bertrand, Daisy Rinaldi, Junhao Wen, Alexandre Routier, Sabrina Fontanella, Philippe Couratier, Olivier Colliot, Alexis Brice, Stanley Durrleman, Olivier Martinaud, and Isabelle Le Ber
Subjects: Pathology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Subcortical atrophy, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, C9orf72, Mutation (genetic algorithm), medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published: 2017
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27. [P4–116]: FRONTOTEMPORAL LOBAR DEGENERATIONS, RNAOPATHY LEADING TO PROTEINOPATHIES

Author: Vincent Anquetil, Anne Bertrand, Alexis Brice, Vincent Deramecourt, Clémence Fournier, Luc Buée, Agnès Camuzat, Charles Duyckaerts, Mathieu Barbier, Isabelle Le Ber, Valérie Buée-Scherrer, Nicolas Sergeant, and Pierre de la Grange
Subjects: 0303 health sciences, 03 medical and health sciences, Psychiatry and Mental health, Cellular and Molecular Neuroscience, 0302 clinical medicine, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology, 030217 neurology & neurosurgery, 030304 developmental biology
Published: 2017
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28. A unique common ancestor introduced P301L mutation in MAPT gene in frontotemporal dementia patients from Barcelona (Baix Llobregat, Spain)

Author: Albert Lladó, Oriol Grau-Rivera, Raquel Sánchez-Valle, Ierai Fernández de Retana, Sergi Borrego, Ramón Reñé, Paola Caroppo, Giacomina Rossi, Leire Palencia-Madrid, Ellen Gelpi, Alexis Brice, Marian M. de Pancorbo, Veronica Redaelli, Isabelle Le Ber, Mircea Balasa, Anna Antonell, Consuelo Almenar, Agnès Camuzat, and Isabel Hernández
Subjects: 0301 basic medicine, Aging, tau Proteins, Biology, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Gene, Ancestor, Genetics, General Neuroscience, Haplotype, medicine.disease, 030104 developmental biology, Spain, Healthy individuals, Frontotemporal Dementia, Mutation (genetic algorithm), Mutation, Neurology (clinical), Geriatrics and Gerontology, 030217 neurology & neurosurgery, Developmental Biology, Frontotemporal dementia, Founder effect
Abstract: The County of Baix Llobregat (Barcelona, Catalonia, Spain) presents a high prevalence of familial frontotemporal dementia (FTD) in the presence of P301L mutation in the MAPT gene. To evaluate a possible unique founder effect of P301L, and its age, the analysis of 20 single-nucleotide polymorphisms covering 50 kb and 12 single-nucleotide polymorphisms located along 30 Mb around the mutation was performed by developing 2 multiplex single-base extension reactions. In addition, families with affected and healthy individuals from France and Italy were analyzed. The FTD-affected individuals from Barcelona carried the same 50-kb haplotype linked to P301L mutation, suggesting a unique common ancestor, as opposed to French patients. Italian patients are also probably descendants of a unique ancestor, which would be different from that of Barcelona. Diversity of 30-Mb haplotypes found in Barcelona and the inference of the mutation age in these populations, among other reasons, suggest that prevalence of FTD linked to P301L MAPT mutation is the result of a locally originated mutation.
Published: 2016

29. Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in theTITF1/NKX2-1gene

Author: Marilyn Tallot, Ralph Epaud, Marie Vidailhet, Thierry Billette de Villemeur, Agnès Camuzat, Jacques Motte, Isabelle Vuillaume, Damien Sanlaville, David Devos, Isabelle Kemlin, Perrine Charles, Isabelle Caubel, Laurence Jonard, Diane Doummar, Sandra Chantot-Bastaraud, Alexandra Durr, Cyril Goizet, Laurence Lion-François, Emmanuel Roze, Domitille Gras, Loïc Guillot, Diana Rodriguez, Marie-Laure Moutard, Malek Louha, Jeanette Koht, Bénédicte Héron, and Michel Polak
Subjects: Male, Thyroid Nuclear Factor 1, Pediatrics, Movement disorders, DNA Mutational Analysis, Respiratory Tract Diseases, Tetrabenazine, Chromosome Disorders, Neuropsychological Tests, Age of Onset, Child, Genes, Dominant, Adrenergic Uptake Inhibitors, Nuclear Proteins, Prognosis, Hypotonia, Psychiatry and Mental health, Phenotype, Treatment Outcome, Child, Preschool, Female, France, medicine.symptom, medicine.drug, Adult, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Tics, Protein Array Analysis, Benign hereditary chorea, Chorea, Internal medicine, mental disorders, Congenital Hypothyroidism, medicine, Humans, business.industry, Infant, medicine.disease, nervous system diseases, Endocrinology, Attention Deficit Disorder with Hyperactivity, Mutation, Surgery, Neurology (clinical), Cognition Disorders, business, Myoclonus, Follow-Up Studies, Transcription Factors
Abstract: Background Benign hereditary chorea (BHC) is a rare autosomal dominant disorder characterised by childhood onset that tends to improve in adulthood. The associated gene, NKX2-1 (previously called TITF1 ), is essential for organogenesis of the basal ganglia, thyroid and lungs. The aim of the study was to refine the movement disorders phenotype. We also studied disease course and response to therapy in a large series of genetically proven patients. Methods We analysed clinical, genetic findings and follow-up data in 28 NKX2-1 mutated BHC patients from 13 families. Results All patients had private mutations, including seven new mutations, three previously reported mutations and three sporadic deletions encompassing the NKX2-1 gene. Hypotonia and chorea were present in early infancy, with delayed walking ability (25/28); dystonia, myoclonus and tics were often associated. Attention deficit hyperactivity disorder (ADHD) was present in seven. Among the 14 patients followed-up until adulthood, nine had persistent mild chorea, two had near total resolution of chorea but persistent disabling prominent myoclonus and three recovered completely. Learning difficulties were observed in 20/28 patients, and three had mental retardation. Various combinations of BHC, thyroid (67%) and lung (46%) features were noted. We found no genotype–phenotype correlation. A rapid and sustained beneficial effect on chorea was obtained in 5/8 patients treated with tetrabenazine. Conclusion Early onset chorea preceded by hypotonia is suggestive of BHC. Associated thyroid or respiratory disorders further support the diagnosis and call for genetic studies. Tetrabenazine may be an interesting option to treat disabling chorea.
Published: 2012
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30. The PSP-associated MAPT H1 subhaplotype in Guadeloupean atypical Parkinsonism

Author: Merle Ruberg, Agnès Camuzat, Annie Lannuzel, Josué Feingold, Alexis Brice, Marc Romana, and Alexandra Durr
Subjects: Genetics, 0303 health sciences, Linkage disequilibrium, Parkinsonism, Locus (genetics), Single-nucleotide polymorphism, Biology, medicine.disease, eye diseases, Progressive supranuclear palsy, 03 medical and health sciences, 0302 clinical medicine, Neurology, medicine, Atypical Parkinsonism, Neurology (clinical), Genetic risk, Allele, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: The aim of this study was to determine whether the H1 subhaplotype in MAPT associated with progressive supranuclear palsy (PSP) in Caucasians confers risk for PSP-like atypical parkinsonism in Guadeloupe, a tauopathy. Guadeloupean controls and patients with atypical and idiopathic parkinsonism and ethnically and age-matched controls were genotyped for H1 and H2 alleles, then for the H1 subhaplotype associated with PSP in Caucasians, using previously described haplotype-tagging single nucleotide polymorphisms (Ht-SNPs) in linkage disequilibrium at the MAPT locus. Most Guadeloupean controls and patients were homozygous for the H1 allele; only 5% were heterozygous for the H2 allele, consistent with the European contribution to the racial admixture in Guadeloupe, but equivalent to the frequency found in Caucasian PSP patients. The frequencies of the Ht-SNPs used to determine the PSP-associated H1 subhaplotype in both Guadeloupean controls and parkinsonians were similar, indicating that the H1 subhaplotype associated with PSP in Caucasians was not a risk factor for PSP-like atypical parkinsonism in Guadeloupe. Interestingly, they were also similar to the frequencies in Caucasian PSP patients. The major H1 subhaplotype in Guadeloupe, determined by analysis of linkage desequibrium, differed from the major Caucasian subhaplotype, but corresponded to minor alleles previously described. © 2008 Movement Disorder Society
Published: 2008
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31. Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study

Author: Valérie Hahn-Barma, Bruno Dubois, Jean-Charles Lambert, Dominique Campion, Serge Bakchine, Agnès Camuzat, Christine Van Broeckhoven, Serge Belliard, Michèle Puel, Patrice Verpillat, Eric Guedj, Alexis Brice, Fabienne Clot, Marie-Odile Habert, Isabelle Le Ber, Jacqueline Mikol, Pascal Lejeune, Ftd-Mnd, Julie van der Zee, Mustapha Ghanim, Didier Hannequin, Vincent Deramecourt, Christian Meyrignac, Martine Vercelletto, Anne Rovelet-Lecrux, Florence Pasquier, Lucette Lacomblez, Vincent de La Sayette, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Department of Genetics, University Hospital, Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service Central de Biophysique et de Médecine Nucléaire, Hôpital de la Timone [CHU - APHM] (TIMONE), Centre des Maladies Cognitives et Comportementales [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Antwerpen, Université de Reims Champagne-Ardenne (URCA), Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Fédération des Maladies du Système Nerveux, 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), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], 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), Service d′Anatomie et de Cytologie Pathologiques [Lariboisiere], Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroendocrinologie et physiopathologie neuronale, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Centre Hospitalier Intercommunal, Centre Hospitalier Départemental, Laboratoire de Neuropsychologie, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de neurologie [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Clinique neurologique, Hôpital Laennec, Service de neurologie, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine nucléaire [CHU Pitié-Salpétrière], Neuro-anatomie fonctionnelle du comportement et de ses troubles, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre du Langage et de Neuropsychologie, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-06-MRAR-005-01, ANR, Département de neurologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Normandie Université (NU)-Normandie Université (NU)-École Pratique des Hautes Études (EPHE), Université de Rennes (UR), French research Network on FTD/FTD-MND, and Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Subjects: Male, Pathology, Neuropsychological Tests, MESH: Epidemiologic Methods, MESH: Aphasia, Primary Progressive, Apraxia, MESH: Magnetic Resonance Imaging, Primary progressive aphasia, Progranulins, MESH: Aged, 80 and over, 0302 clinical medicine, MESH: Motor Neuron Disease, Corticobasal degeneration, Age of Onset, MESH: Brain Mapping, MESH: Heterozygote, Aged, 80 and over, MESH: Aged, Brain Mapping, 0303 health sciences, MESH: Middle Aged, Parkinsonism, Brain, MESH: Neuropsychological Tests, Middle Aged, Magnetic Resonance Imaging, MESH: Dementia, 3. Good health, Phenotype, Disease Progression, Intercellular Signaling Peptides and Proteins, Female, MESH: Disease Progression, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Psychology, Haploinsufficiency, Frontotemporal dementia, Adult, Heterozygote, medicine.medical_specialty, MESH: Mutation, MESH: Age of Onset, MESH: Phenotype, MESH: Brain, 03 medical and health sciences, medicine, Humans, Dementia, Motor Neuron Disease, MESH: Intercellular Signaling Peptides and Proteins, Aged, 030304 developmental biology, MESH: Humans, Lewy body, MESH: Adult, medicine.disease, MESH: Male, MESH: Cognition Disorders, Aphasia, Primary Progressive, Mutation, Neurology (clinical), Cognition Disorders, Epidemiologic Methods, MESH: Female, 030217 neurology & neurosurgery
Abstract: Frontotemporal dementia (FTD), characterized by behavioural and language disorders, is a clinically, genetically and pathologically heterogeneous group of diseases. The most recently identified of the four known genes is GRN, associated with 17q-linked FTD with ubiquitin-immunoreactive inclusions. GRN was analysed in 502 probands with frontal variant FTD (fvFTD), FTD with motoneuron disease (FTD-MND), primary progressive aphasia (PPA) and corticobasal degeneration syndrome (CBDS). We studied the clinical, neuropsychological and brain perfusion characteristics of mutation carriers. Eighteen mutations, seven novel were found in 24 families including 32 symptomatic mutation carriers. No copy number variation was found. The phenotypes associated with GRN mutations vary greatly: 20/32 (63%) carriers had fvFTD, the other (12/32, 37%) had clinical diagnoses of PPA, CBDS, Lewy body dementia or Alzheimer's disease. Parkinsonism developed in 13/32 (41%), visual hallucinations in 8/32 (25%) and motor apraxia in 5/21 (24%). Constructional disorders were present in 10/21 (48%). Episodic memory disorders were frequent (16/18, 89%), consistent with hippocampal amnestic syndrome in 5/18 (28%). Hypoperfusion was observed in the hippocampus, parietal lobe and posterior cingulate gyrus, as well as the frontotemporal cortices. The frequency of mutations according to phenotype was 5.7% (20/352) in fvFTD, 17.9% (19/106) in familial forms, 4.4% in PPA (3/68), 3.3% in CBDS (1/30). Hallucinations, apraxia and amnestic syndrome may help differentiate GRN mutation carriers from others FTD patients. Variable phenotypes and neuropsychological profiles, as well as brain perfusion profiles associated with GRN mutations may reflect different patterns of neurodegeneration. Since all the mutations cause a progranulin haploinsufficiency, additional factors probably explain the variable clinical presentation of the disease.
Published: 2008
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32. Defining the spectrum of frontotemporal dementias associated with TARDBP mutations

Author: Isabelle Le Ber, Agnès Camuzat, Véronique Golfier, John C. van Swieten, Serena Lattante, Serge Belliard, Alexis Brice, Bernard Laurent, Sophie Auriacombe, Stéphanie Millecamps, Bruno Dubois, Lena Guillot-Noel, Catherine Thomas-Antérion, Philippe Couratier, Tsz Hang Wong, Paola Caroppo, Fabienne Clot, Marc Teichmann, The Foundation 'Carlo Besta' Institute of Neurology ( IRCCS ), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Laboratoire d'Etude des Mécanismes Cognitifs ( EMC ), Université Lumière - Lyon 2 ( UL2 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Lumière - Lyon 2 ( UL2 ), Erasmus Medical Center Rotterdam, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Etude des Mécanismes Cognitifs (EMC), Université Lumière - Lyon 2 (UL2), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Neurology
Subjects: 0301 basic medicine, Proband, Genetic counseling, Settore MED/03 - GENETICA MEDICA, TARDBP, Article, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Genotype, Medicine, Family history, frontotemporal dementias, Genetics (clinical), Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, medicine.disease, Penetrance, Phenotype, 3. Good health, 030104 developmental biology, Neurology (clinical), business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract: International audience; Objectives: We describe the largest series of patients with TARDBP mutations presenting with frontotemporal dementia (FTD) and review the cases in the literature to precisely characterize FTD diseases associated with this genotype.Methods: The phenotypic characteristics of 29 TARDBP patients, including 10 new French and Dutch cases and 19 reviewed from the literature, were evaluated.Results: The most frequent phenotype was a behavioral variant frontotemporal dementia (bvFTD), but a significant proportion (40%) of our patients had semantic (svFTD) or nonfluent variants (nfvFTD) at onset; and svFTD was significantly more frequent in TARDBP carriers than in other FTD genotypes (p < 0.001). Remarkably, only a minority (40%) of our patients secondarily developed amyotrophic lateral sclerosis (ALS). Two patients carried a homozygous mutation but strikingly different phenotypes (bvFTD and ALS) indicating that homozygosity does not result in a specific phenotype. Earlier age at onset in children than parent's generations, mimicking an apparent “anticipation” (21.8 ± 9.3 years, p = 0.001), and possible reduced penetrance were present in most families.Conclusions: This study enlarges the phenotypic spectrum of TARDBP and will have important clinical implications: (1) FTD can be the only clinical manifestation of TARDBP mutations; (2) Initial language or semantic disorders might be indicative of a specific genotype; (3) Mutations should be searched in all FTD phenotypes after exclusion of major genes, even in the absence of ALS in the proband or in family history; (4) reduced penetrance and clinical variability should be considered to deliver appropriate genetic counseling.
Published: 2016
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33. Clinical and neuropathologic study of a French family with a mutation in the neuroserpin gene

Author: Alexis Brice, C. Meyrignac, Isabelle Gourfinkel-An, Michel Baulac, Charles Duyckaerts, Agnès Camuzat, and Peter Sonderegger
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Cerebellum, Genotype, Mutation, Missense, Caudate nucleus, Progressive myoclonus epilepsy, Biology, Inclusion bodies, Neuroserpin, medicine, Humans, Point Mutation, Missense mutation, Familial encephalopathy with neuroserpin inclusion bodies, Serpins, Inclusion Bodies, Point mutation, Neuropeptides, Exons, Myoclonic Epilepsies, Progressive, medicine.disease, Frontal Lobe, Pedigree, Phenotype, medicine.anatomical_structure, Amino Acid Substitution, Dementia, Female, France, Neurology (clinical), Neuroscience, Switzerland
Abstract: Familial encephalopathy with neuroserpin inclusion bodies is a recently described neurodegenerative disease that is responsible for progressive myoclonic epilepsy or presenile dementia. In a French family with the S52R mutation of the neuroserpin gene, progressive myoclonic epilepsy was associated with a frontal syndrome. The typical cerebral inclusions (Collins bodies) were abundant in the frontal cortex and in the head of the caudate nucleus but spared the cerebellum.
Published: 2007
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34. Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism?

Author: Alain Destée, Alexis Brice, Nawal Benammar, Alexandra Durr, François Sellal, A. M. Bonnet, P. Charles, Giovanni Stevanin, Suzanne Lesage, I. Le Ber, Agnès Camuzat, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Clinique Neurologique, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), ANR, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Male, MESH: DNA Repeat Expansion, MESH: Risk Assessment, 0302 clinical medicine, Degenerative disease, Autosomal dominant cerebellar ataxia, Risk Factors, MESH: Risk Factors, Prevalence, MESH: Nerve Tissue Proteins, MESH: Heterozygote, MESH: Aged, Genetics, 0303 health sciences, DNA Repeat Expansion, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, Parkinsonism, MESH: Genetic Predisposition to Disease, Parkinson Disease, Middle Aged, LRRK2, Phenotype, Pedigree, Ataxins, Spinocerebellar ataxia, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], France, medicine.symptom, Heterozygote, MESH: Pedigree, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, MESH: Prevalence, Aged, Repetitive Sequences, Nucleic Acid, 030304 developmental biology, MESH: Repetitive Sequences, Nucleic Acid, MESH: Humans, Cerebellar ataxia, medicine.disease, MESH: Male, nervous system diseases, MESH: France, Neurology (clinical), Trinucleotide repeat expansion, MESH: Female, MESH: Parkinson Disease, 030217 neurology & neurosurgery
Abstract: Background: Autosomal dominant parkinsonism (ADP) is caused in a large percentage of familial and sporadic cases by mutations in the LRRK2 gene, particularly G2019S. It is also caused by mutations in genes associated with autosomal dominant cerebellar ataxia (ADCA), notably CAG/CAA repeat expansions in SCA2.Methods: We screened 164 families with ADP for expansions in the SCA2, 3, and 17 genes and for the G2019S mutation in LRRK2. The SCA2 CAG/CAA repeat expansion was sequenced to determine its structure. The phenotypes of patients with ADP caused by the SCA2, LRRK2, and unknown mutations were compared, as well as those of SCA2 patients with interrupted or uninterrupted expansions of the same size.Results: Three French ADP families had SCA2 mutations. The expansions ranged from 37 to 39 repeats and were interrupted and stable upon transmission. All patients (n = 9) had levodopa-responsive parkinsonism without cerebellar signs. They had significantly more symmetric signs and less rigidity than ADP caused by the G2019S mutation in LRRK2 or by unknown mutations. Interestingly, two sisters carrying both the SCA2 and the G2019S LRRK2 mutations had markedly earlier onset than their mother with only SCA2. In contrast, similar-sized but uninterrupted repeats were associated with ADCA in which cerebellar ataxia was constant and associated only rarely with one or more mild parkinsonian signs.Conclusion: These results suggest that the configuration of the SCA2 CAG/CAA repeat expansions plays an important role in phenotype variability. Uninterrupted SCA2 repeat expansions found in families with autosomal dominant cerebellar ataxia result in somatic mosaicism and produce large hairpin RNAs, which may interact with double-stranded RNA-binding proteins. These characteristics are modified by interruption of the SCA2 repeat expansion as found in families with autosomal dominant parkinsonism.
Published: 2007
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35. TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts

Author: Isabelle Le Ber, Anne De Septenville, Stéphanie Millecamps, Agnès Camuzat, Paola Caroppo, Philippe Couratier, Frédéric Blanc, Lucette Lacomblez, François Sellal, Marie-Céline Fleury, Vincent Meininger, Cécile Cazeneuve, Fabienne Clot, Olivier Flabeau, Eric LeGuern, Alexis Brice, Sophie Auriacombe, Mira Didic, Bruno Dubois, Véronique Golfier, Didier Hannequin, Richard Levy, Bernard-François Michel, Florence Pasquier, Catherine Thomas-Anterion, Michèle Puel, François Salachas, and Martine Vercelletto
Subjects: Aging, Mutation rate, Protein Serine-Threonine Kinases, medicine.disease_cause, Cohort Studies, Mutation Rate, C9orf72, mental disorders, medicine, Missense mutation, Humans, Amyotrophic lateral sclerosis, Loss function, Genetic Association Studies, Optineurin, Genetics, Mutation, business.industry, General Neuroscience, Amyotrophic Lateral Sclerosis, nutritional and metabolic diseases, medicine.disease, nervous system diseases, Frontotemporal Dementia, Neurology (clinical), France, Geriatrics and Gerontology, business, Developmental Biology, Frontotemporal dementia
Abstract: TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4%-4% of ALS. Considering the strong genetic overlap existing between frontotemporal dementia (FTD) and ALS, we have evaluated the frequencies of TBK1 mutations in a cohort of French FTD and of ALS patients. We identified 5 LoF mutations, in 4 FTD-ALS and 1 ALS patients. We also identified 5 heterozygous missense variants, predicted to be deleterious, in 1 isolated FTD, 1 FTD-ALS, and 3 ALS cases. Our results demonstrate that TBK1 loss-of-function mutations are more frequent in patients with FTD-ALS (10.8%) than in isolated ALS. TBK1 should thus also be sequenced, after exclusion of C9orf72 mutation, in patients presenting FTD, particularly in cases secondarily associated with ALS.
Published: 2015

36. Age at onset variance analysis in spinocerebellar ataxias: A study in a Dutch-French cohort

Author: Bart P.C. van de Warrenburg, Richard J. Sinke, Alexandra Durr, Alexis Brice, Giovanni Stevanin, Agnès Camuzat, Harrie Hendriks, Berry Kremer, and Martin C A van Zuijlen
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, business.industry, Physiology, medicine.disease, Neurology, Cohort, Genotype, Spinocerebellar ataxia, Medicine, Neurology (clinical), Analysis of variance, Allele, Age of onset, business, Trinucleotide repeat expansion, Cohort study
Abstract: In dominant spinocerebellar ataxias (SCAs), the issue of whether non-CAG dependent factors contribute to onset age remains unsettled. Data on SCA genotype, onset age, normal/expanded CAG repeat length, sex of the patient and transmitting parent, and family details were available from 802 patients. Based on the model [log(10) (age at onset) = k - b CAG(exp) + epsilon], we examined changes in adjusted R(2) and residual standard error following incorporation of the other factors in this model. The expanded repeat explained 44.3 to 74.9% of onset age variance, although this was less than 50% in SCA3 and SCA6, implicating a large effect of non-CAG factors. The relation between onset age and CAG repeat was similar for SCA1, 3, 6, and 7, but different for SCA2, pointing to different polyglutamine effects in SCA2. For SCA2 and SCA3, 17.1 and 45.5% of onset age variance, respectively, were explained by currently (unidentified) familial factors. We found a significant contribution of the nonexpanded allele in SCA1 and SCA6. Besides polyglutamine motif (determined by the expanded CAG repeat length), we identified the following age at onset modifiers: protein context in SCA2; familial factors in SCA2 and SCA3; and the nonexpanded CAG repeat in SCA1 and SCA6.
Published: 2005
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37. Huntington's disease-like phenotype due to trinucleotide repeat expansions in the TBP and JPH3 genes

Author: Chankranira San, Cecile Jeannequin, Robert Bellance, Junko Takahashi, Agnès Camuzat, Hiroto Fujigasaki, Anne-Sophie Lebre, Alexandra Durr, Alexis Brice, Catherine Dodé, and Giovanni Stevanin
Subjects: Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Prions, Nerve Tissue Proteins, Biology, Polymerase Chain Reaction, PRNP, Huntington's disease, Autosomal dominant cerebellar ataxia, mental disorders, medicine, Humans, Allele, Genetics, Dentatorubral-pallidoluysian atrophy, Genetic heterogeneity, Membrane Proteins, Middle Aged, TATA-Box Binding Protein, medicine.disease, Penetrance, nervous system diseases, Huntington Disease, Phenotype, Female, Neurology (clinical), Trinucleotide Repeat Expansion, Trinucleotide repeat expansion
Abstract: Summary We report a group of 252 patients with a Huntington’s disease-like (HDL) phenotype, including 60 with typical Huntington’s disease, who had tested negative for pathological expansions in the IT15 gene, the major mutation in Huntington’s disease. They were screened for repeat expansions in two other genes involved in HDL phenotypes: those encoding the junctophilin-3 (JPH3/HDL2) and prion (PRNP/HDL1) proteins. In addition, because of the clinical overlap between patients with HDL disease and autosomal dominant cerebellar ataxia or dentatorubral and pallidoluysian atrophy (DRPLA), we investigated trinucleotide repeat expansions in genes encoding the TATA-binding protein (TBP/SCA17) and atrophin-1 (DRPLA). Two patients carried 43 and 50 uninterrupted CTG repeats in the JPH3 gene. Two other patients had 44 and 46 CAA/ CAG repeats in the TBP gene. Patients with expansions in the TBP or JPH3 genes had HDL phenotypes indistinguishable from Huntington’s disease. Taking into account patients with typical Huntington’s disease, their frequencies were evaluated as 3% each in our series of typical HDL patients. Interestingly, incomplete penetrance of the 46 CAA/CAG repeat in the TBP gene was observed in a 59-year-old transmitting, but healthy, parent. Furthermore, we report a new configuration of the expanded TBP allele, with 11 repeats on the first polymorphic stretch of CAGs. Expansions in the DRPLA gene and insertions in the PRNP gene were not found in our group of patients. Further genetic heterogeneity of the HDL phenotype therefore exists.
Published: 2003
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38. Apolipoprotein E gene in frontotemporal dementia: an association study and meta-analysis

Author: Agnès Camuzat, Patrice Verpillat, Michèle Puel, Alexis Brice, Didier Hannequin, Olivier Moreaud, Françoise Clerget-Darpoux, Dominique Campion, Lucette Lacomblez, Bruno Dubois, Mira Didic, Véronique Golfier, Serge Belliard, and Catherine Thomas-Antérion
Subjects: Adult, Male, Apolipoprotein E, Oncology, medicine.medical_specialty, White People, Apolipoproteins E, Internal medicine, mental disorders, Genotype, Genetics, medicine, Humans, Allele, Risk factor, Allele frequency, Genetics (clinical), Aged, business.industry, Case-control study, Odds ratio, Middle Aged, medicine.disease, Case-Control Studies, Dementia, Female, France, business, Frontotemporal dementia
Abstract: No definite genetic risk factor of non-monogenic frontotemporal dementia (FTD) has yet been identified. Several groups have examined the potential association of FTD with the apolipoprotein E (APOE) gene, but the results are inconsistent. Our objective was to determine whether APOE is a risk factor of FTD, using the largest series of patients with FTD and controls analysed so far (94 unrelated patients and 392 age and sex-matched controls), and a meta-analysis. Homozygosity for the E2E2 genotype was significantly associated with FTD (odds ratio (OR)=11.3; P=0.033, exact test). After stratification on familial history (FH) for FTD, the OR for E2E2 was still found significant when analysing only patients with a positive FH (OR=23.8; P=0.019). The meta-analysis, using 10 case-control studies with available genotype or allele information, comprising a total of 364 FTD patients and 2671 controls, including the patients of the present study, did not reach statistical significance even if the E2E2 genotype was more frequent in patients than in controls (0.018 vs 0.006, respectively). Because of studies heterogeneity (Mantel-Haenszel statistics: P=0.004), we analysed on one hand the neuropathologically-confirmed studies, and on the other hand the clinical-based studies. In the neuropathologically-confirmed studies (Mantel-Haenszel statistics: P=ns), we found a significant increase of the E2 allele frequency in FTD patients (OR[E2 vs E3]=2.01; 95% CI=1.02-3.98; P=0.04). The same result was found in the clinical-based studies, but studies heterogeneity remained. No result was significant with the E4 allele. The E2 allele seems so to be a risk factor of FTD whereas this allele is associated with the lowest risk in Alzheimer's disease. If this finding was confirmed, it could provide new insights into the mechanisms of differential risk related to APOE in neurodegenerative diseases.
Published: 2002
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39. Guadeloupean parkinsonism: a cluster of progressive supranuclear palsy‐like tauopathy

Author: Nicolas Sergeant, Susan E. Daniel, Andrew J. Lees, Alexis Brice, Dominique Caparros-Lefebvre, Agnès Camuzat, Annie Lannuzel, Eduardo Tolosa, André Delacourte, and Charles Duyckaerts
Subjects: Male, medicine.medical_specialty, Pathology, Neurology, DNA Mutational Analysis, tau Proteins, Progressive supranuclear palsy, Parkinsonian Disorders, medicine, Cluster Analysis, Humans, Protein Isoforms, Dementia, Corticobasal degeneration, Genetic Testing, Amyotrophic lateral sclerosis, Guadeloupe, Aged, Neurons, Polymorphism, Genetic, Parkinsonism, Brain, Middle Aged, medicine.disease, nervous system diseases, Mutation, Female, Supranuclear Palsy, Progressive, Neurology (clinical), Tauopathy, Psychology, Frontotemporal dementia
Abstract: An unusually high frequency of atypical Parkinson syndrome has been delineated over the last 5 years in the French West Indies. Postural instability with early falls, prominent frontal lobe dysfunction and pseudo-bulbar palsy were common and three-quarters of the patients were L-dopa unresponsive. One-third of all patients seen had probable progressive supranuclear palsy (PSP). This new focus of atypical parkinsonism is reminiscent of the one described in Guam and may be linked to exposure to tropical plants containing mitochondrial complex I inhibitors (quinolines, acetogenins, rotenoids). Two hundred and twenty consecutive patients with Parkinson's syndrome seen by the neurology service at Pointe à Pitre, Guadeloupe University Hospital were studied. Currently accepted operational clinical criteria for Parkinson's syndromes were applied. The pathological findings of three patients who came to autopsy are reported. Fifty-eight patients had probable PSP, 96 had undetermined parkinsonism and 50 had Parkinson's disease, 15 had amyotrophic lateral sclerosis with parkinsonism and one had probable multiple system atrophy. All three PSP patients in whom post-mortem study was performed had early postural instability, gaze palsy and parkinsonian symptoms, followed by a frontolimbic dementia and corticobulbar signs. Neuropathological examination showed an accumulation of tau proteins, predominating in the midbrain. There was an exceptionally large accumulation of neuropil threads in Case 1. Biochemical studies detected a major doublet of pathological tau at 64 and 69 kDa in brain tissue homogenates. All cases were homozygous for the H1 tau haplotype, but no mutation of the tau gene was observed. Clinical, neuropathological and biochemical features were compatible with the diagnosis of PSP, although some unusual pathological features were noted in Case 1. A cluster of cases presenting with atypical parkinsonism is reported. Guadeloupean parkinsonism may prove to be a tauopathy identical or closely related to PSP.
Published: 2002
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40. G303V tau mutation presenting with progressive supranuclear palsy-like features

Author: Agnès Camuzat, Emmanuel Broussolle, Alice Poisson, Jérôme Honnorat, Ariane Choumert, Isabelle Le Ber, and Stéphane Thobois
Subjects: Adult, Family Health, Family health, Genetics, business.industry, DNA Mutational Analysis, Glycine, Valine, tau Proteins, Exons, Middle Aged, medicine.disease, Progressive supranuclear palsy, Exon, Neurology, Humans, Medicine, Supranuclear Palsy, Progressive, Neurology (clinical), Tau mutation, business
Published: 2011
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41. Posterior cortical atrophy as an extreme phenotype of GRN mutations

Author: Agnès Camuzat, Isabelle Le Ber, Fabienne Clot, Catherine Belin, Bruno Dubois, Foudil Lamari, Paola Caroppo, Didier Maillet, David Grabli, Alexis Brice, Raffaella Migliaccio, and Anne de Septenville
Subjects: Male, Pathology, medicine.medical_specialty, Atrophy, Progranulins, medicine, Posterior cortical atrophy syndrome, Humans, Cerebral atrophy, Cerebral Cortex, Posterior cortical atrophy, Neurodegenerative Diseases, Frontotemporal lobar degeneration, Syndrome, Middle Aged, medicine.disease, Apperceptive agnosia, Pedigree, Phenotype, Mutation, Intercellular Signaling Peptides and Proteins, Neurology (clinical), Alzheimer's disease, Psychology, Neuroscience, Frontotemporal dementia
Abstract: Importance Posterior cortical atrophy (PCA) is characterized by progressive visuoperceptual and visuospatial deficits and commonly considered to be an atypical variant of Alzheimer disease. Mutations of the GRN gene are responsible for a large phenotypic spectrum, but, to our knowledge, the association of PCA with GRN mutations has never been described. Observations We studied a patient presenting with insidious impairment of basic visuoperceptual skills and apperceptive visual agnosia with predominant posterior atrophy corresponding to a visual/ventral variant of PCA. A heterozygous p.Arg110* (c.328C>T) GRN mutation was identified in this patient. Conclusions and Relevance This study extends the clinical spectrum of GRN mutations that may be responsible for a PCA phenotype. The GRN phenotypes overlap other degenerative dementias and highlight the limits of actual nosologic boundaries in dementias. The GRN gene should be analyzed in patients with PCA, particularly when the damage progresses to anterior cerebral regions and a family history of dementia is present.
Published: 2014

42. Extensive white matter involvement in patients with frontotemporal lobar degeneration: think progranulin

Author: Isabelle Le Ber, Foudil Lamari, Didier Hannequin, Lionel Naccache, Fabienne Clot, Anne de Septenville, Alexis Brice, Anne Bertrand, Serge Belliard, Olivier Colliot, Paola Caroppo, Agnès Camuzat, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Service d'Explorations Fonctionnelles Neurologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Service de Neurophysiologie Clinique [CHU Pitié-Salpêtrière], Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], UF Neurométabolique Bioclinique et Génétique [CHU Pitié-Salpêtrière], GRC Neurométabolisme, Université Pierre et Marie Curie - Paris 6 (UPMC), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Service de Neuroradiologie [CHU Pitié-Salpêtrière], Service de Neurologie [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Neuropsychologie cognitive et neuroanatomie fonctionnelles de la mémoire humaine, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Service de Neurophysiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Inria de Paris, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Normandie Université (NU)-Normandie Université (NU)-École Pratique des Hautes Études (EPHE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris
Subjects: Male, Pathology, medicine.medical_specialty, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Cerebrum, MESH: Atrophy, White matter, Atrophy, Progranulins, mental disorders, medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Dementia, Humans, MESH: Intercellular Signaling Peptides and Proteins, Cerebrum, Aged, Cerebral atrophy, MESH: Aged, MESH: Humans, MESH: Middle Aged, business.industry, Parietal lobe, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Frontotemporal lobar degeneration, Middle Aged, medicine.disease, White Matter, Hyperintensity, MESH: Male, medicine.anatomical_structure, MESH: White Matter, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Intercellular Signaling Peptides and Proteins, Neurology (clinical), MESH: Frontotemporal Lobar Degeneration, Frontotemporal Lobar Degeneration, Haploinsufficiency, business, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing
Abstract: International audience; Mutations in the progranulin (GRN) gene are responsible for 20% of familial cases of frontotemporal dementias. All cause haploinsufficiency of progranulin, a protein involved in inflammation, tissue repair, and cancer. Carriers of the GRN mutation are characterized by a variable degree of asymmetric brain atrophy, predominantly in the frontal, temporal, and parietal lobes. We describe 4 GRN mutation carriers with remarkable widespread white matter lesions (WML) associated with lobar atrophy shown on magnetic resonance imaging.; Four GRN mutation carriers (age at onset, 56-65 years) presenting with severe WML were selected from 31 GRN mutation carriers who were followed up in our dementia centers. The WML were predominantly in the frontal and parietal lobes and were mostly confluent, affecting the periventricular subcortical white matter and U-fibers. In all patients, common vascular, metabolic, inflammatory, dysimmune, and mitochondrial disorders were excluded and none had severe vascular risk factors.; Our data suggest that white matter involvement may be linked to progranulin pathological processes in a subset of GRN mutation carriers. The plasma progranulin measurement, which is predictive of GRN mutations, and GRN sequencing should thus be included in investigations of patients with frontotemporal lobar degenerations who show unusual white matter hyperintensities and atrophy on magnetic resonance imaging.
Published: 2014

43. Defining the association of TMEM106B variants among frontotemporal lobar degeneration patients with GRN mutations and C9orf72 repeat expansions

Author: Edor Kabashi, Sophie Rivaud-Péchoux, Alexis Brice, Chiara Fenoglio, Isabelle Le Ber, Daniela Galimberti, Maria Serpente, Fabienne Clot, Agnès Camuzat, Elio Scarpini, and Serena Lattante
Subjects: Male, Aging, Genotype, Chromosome 9, Nerve Tissue Proteins, Disease, Biology, Settore MED/03 - GENETICA MEDICA, medicine.disease_cause, Cohort Studies, Progranulins, C9orf72, mental disorders, medicine, Humans, Amyotrophic lateral sclerosis, Gene, Genetic Association Studies, Aged, Genetics, Mutation, Polymorphism, Genetic, C9orf72 Protein, General Neuroscience, Amyotrophic Lateral Sclerosis, Membrane Proteins, Proteins, FTD, Frontotemporal lobar degeneration, Middle Aged, medicine.disease, rs1990622, nervous system diseases, TMEM106B, Italy, rs3173615, Intercellular Signaling Peptides and Proteins, FTD-ALS, Female, Neurology (clinical), France, Geriatrics and Gerontology, Frontotemporal Lobar Degeneration, Trinucleotide Repeat Expansion, GRN, Developmental Biology
Abstract: TMEM106B was identified as a risk factor for frontotemporal lobar degeneration (FTD) with TAR DNA-binding protein 43 kDa inclusions. It has been reported that variants in this gene are genetic modifiers of the disease and that this association is stronger in patients carrying a GRN mutation or a pathogenic expansion in chromosome 9 open reading frame 72 (C9orf72) gene. Here, we investigated the contribution of TMEM106B polymorphisms in cohorts of FTD and FTD with amyotrophic lateral sclerosis patients from France and Italy. Patients carrying the C9orf72 expansion (n = 145) and patients with GRN mutations (n = 76) were compared with a group of FTD patients (n = 384) negative for mutations and to a group of healthy controls (n = 552). In our cohorts, the presence of the C9orf72 expansion did not correlate with TMEM106B genotypes but the association was very strong in individuals with pathogenic GRN mutations (p = 9.54 × 10(-6)). Our data suggest that TMEM106B genotypes differ in FTD patient cohorts and strengthen the protective role of TMEM106B in GRN carriers. Further studies are needed to determine whether TMEM106B polymorphisms are associated with other genetic causes for FTD, including C9orf72 repeat expansions.
Published: 2014

44. hnRNPA2B1 and hnRNPA1 mutations are rare in patients with 'multisystem proteinopathy' and frontotemporal lobar degeneration phenotypes

Author: Edor Kabashi, Gaël Nicolas, Alexis Brice, Agnès Camuzat, Isabelle Le Ber, Serena Lattante, Didier Hannequin, Ludmila Jornea, Inge Van Bortel, Morwena Latouche, Kawtar Bouya-Ahmed, David Wallon, Anne de Septenville, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [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: Aging, Pathology, medicine.medical_specialty, hnRNPA1, MESH: Mutation, Heterogeneous Nuclear Ribonucleoprotein A1, MESH: Osteitis Deformans, Settore MED/03 - GENETICA MEDICA, medicine.disease_cause, Myositis, Inclusion Body, Cohort Studies, Pathogenesis, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, parasitic diseases, mental disorders, medicine, Amyotrophic lateral sclerosis, Gene, MESH: Cohort Studies, Exome sequencing, MESH: Amyotrophic Lateral Sclerosis, Mutation, business.industry, General Neuroscience, Amyotrophic Lateral Sclerosis, nutritional and metabolic diseases, Frontotemporal lobar degeneration, MESH: Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Osteitis Deformans, hnrRNPA2B1, medicine.disease, MESH: Myositis, Inclusion Body, Phenotype, Multisystem proteinopathy, nervous system diseases, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), MESH: Frontotemporal Lobar Degeneration, ALS, Frontotemporal Lobar Degeneration, Geriatrics and Gerontology, FTLD, business, Developmental Biology
Abstract: International audience; hnRNPA2B1 and hnRNPA1 mutations have been recently identified by exome sequencing in three families presenting with multisystem proteinopathy (MSP), a rare complex phenotype associating frontotemporal lobar degeneration (FTLD), Paget disease of bone (PDB), inclusion body myopathy (IBM), and amyotrophic lateral sclerosis (ALS). No study has evaluated the exact frequency of these genes in cohorts of MSP or FTD patients so far. We sequenced both genes in 17 patients with MSP phenotypes, and in 60 patients with FTLD and FTLD-ALS to test whether mutations could be implicated in the pathogenesis of these disorders. No disease-causing mutation was identified. We conclude that hnRNPA2B1 and hnRNPA1 mutations are rare in MSP and FTLD spectrum of diseases, although further investigations in larger populations are needed.
Published: 2014

45. SCA12 is a rare locus for autosomal dominant cerebellar ataxia: A study of an Indian family

Author: Russell L. Margolis, Cecilia Zander, Susan E. Holmes, Ishwar C. Verma, Ish Anand, Alexis Brice, Renu Saxena, Hiroto Fujigasaki, Alexandra Durr, Christopher A. Ross, Laure Jamot, Anne-Sophie Lebre, and Agnès Camuzat
Subjects: Genetics, congenital, hereditary, and neonatal diseases and abnormalities, Locus (genetics), Biology, medicine.disease, PPP2R2B, Degenerative disease, Neurology, Autosomal dominant cerebellar ataxia, medicine, Spinocerebellar ataxia, Neurology (clinical), Allele, Trinucleotide repeat expansion, Gene
Abstract: Spinocerebellar ataxia 12 (SCA12) is an autosomal dominant cerebellar ataxia (ADCA) described in a single family with a CAG repeat expansion in the PPP2R2B gene. We screened 247 index cases, including 145 families with ADCA, for this expansion. An expanded repeat ranging from 55 to 61 triplets was detected in 6 affected and 3 unaffected individuals at risk in a single family from India. The association of the PPP2R2B CAG repeat expansion with disease in this new family provides additional evidence that the mutation is causative.
Published: 2001
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46. Screening of the THAP1 gene in patients with early-onset dystonia: myoclonic jerks are part of the dystonia 6 phenotype

Author: Marie Vidailhet, Agnès Camuzat, Alexis Brice, Chan San, Pierre Krystkowiak, Fabienne Clot, Pierre Pollak, Pierre Burbaud, Emmanuel Roze, Magali Aya, David Grabli, Alexandra Durr, Pascal Derkinderen, Luc Defebvre, Philippe Damier, and Eric LeGuern
Subjects: Adult, Male, Adolescent, Myoclonic Jerk, Mutation, Missense, medicine.disease_cause, Bioinformatics, Frameshift mutation, Cellular and Molecular Neuroscience, Exon, Myoclonus/genetics/physiopathology, otorhinolaryngologic diseases, Genetics, medicine, Humans, Dystonia Musculorum Deformans, Frameshift Mutation, Gene, Genetics (clinical), Aged, Sequence Deletion, Dystonia, Mutation, business.industry, Dystonia Musculorum Deformans/genetics/physiopathology, Middle Aged, medicine.disease, ddc:616.8, nervous system diseases, Nuclear Proteins/genetics, Phenotype, Amino Acid Substitution, Codon, Nonsense, Apoptosis Regulatory Proteins/genetics, Female, medicine.symptom, business, Myoclonus, DNA-Binding Proteins/genetics
Abstract: Mutations in the THAP1 gene are responsible for an autosomal dominant form of primary torsion dystonia 6 (DYT6) [1]. Patients with DYT6 are characterized usually by childhoodor early-adulthood-onset dystonia, affecting brachial, cervical, or cranial muscles with possible progression towards generalized dystonia [2–5]. We analyzed the three exons of the THAP1 gene by direct sequencing in 113 primary dystonia cases from France, European countries, and North Africa. Familial or isolated cases with primary dystonias with early-onset ( C/p.Ser6Pro and c.215T>G/p.Leu72Arg) which affect residues that are highly conserved across
Published: 2010
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47. Segregation of a Missense Mutation in the Microtubule-Associated Protein Tau Gene with Familial Frontotemporal Dementia and Parkinsonism

Author: C. Penet, Agnès Camuzat, Cosette Martin, Patrice Verpillat, Bruno Dubois, Thierry Frebourg, Yves Agid, Dominique Campion, Alexis Brice, Pascale Saugier-Veber, Cécile Dumanchin, Françoise Charbonnier, and Didier Hannequin
Subjects: Adult, Male, Candidate gene, Tau protein, Mutation, Missense, tau Proteins, Frontotemporal dementia and parkinsonism linked to chromosome 17, Exon, Genetics, medicine, Humans, Dementia, Missense mutation, Age of Onset, Molecular Biology, Genetics (clinical), Aged, biology, Parkinsonism, Parkinson Disease, General Medicine, Middle Aged, medicine.disease, Temporal Lobe, Frontal Lobe, Pedigree, biology.protein, Female, Frontotemporal dementia
Abstract: Frontotemporal dementia and parkinsonism (FTDP) is the second most common cause of neurodegenerative dementia after Alzheimer's disease. Recently, several kindreds with an autosomal dominant form of FTDP have been reported and in some families the pathological locus was mapped to a 2 cM interval on 17q21-22. The MAPT gene, located on 17q21 and coding for the human microtubule-associated protein tau, is a strong candidate gene, since tau-positive neuronal inclusions have been observed in brains from some FTDP patients. Direct sequencing of the MAPT exonic sequences in 21 French FTDP families revealed in six index cases the same missense mutation in exon 10 resulting in a Pro-->Leu change at amino acid 301. Co-segregation of this mutation with the disease was demonstrated by restriction fragment analysis in two families for which several affected relatives were available. The Pro301Leu mutation was not observed in either 50 unrelated French controls or in 11 patients with sporadic frontotemporal dementia. This mutation, which occurs in the second microtubule-binding domain of the MAPT protein, is likely to have a drastic functional consequence. The observation of this mutation in several FTDP families might suggest that disruption of binding of MAPT protein to the microtubule is a key event in the pathogenesis of FTDP.
Published: 1998
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48. Partial deletions of the GRN gene are a cause of frontotemporal lobar degeneration

Author: Isabelle Le Ber, Agnès Camuzat, Foudil Lamari, Ludmila Jornea, Dominique Campion, Eric LeGuern, Fabienne Clot, Anne Rovelet-Lecrux, Béatrice Laudier, Anne de Septenville, Alexis Brice, Boris Keren, Paola Caroppo, Cécile Cazeneuve, Sandrine Noël, and A Michon
Subjects: Genetics, Breakpoint, Intron, Loss of Heterozygosity, Frontotemporal lobar degeneration, Middle Aged, Biology, medicine.disease, Molecular biology, Pedigree, Frameshift mutation, Loss of heterozygosity, Cellular and Molecular Neuroscience, Exon, Progranulins, mental disorders, medicine, Humans, Intercellular Signaling Peptides and Proteins, Multiplex ligation-dependent probe amplification, Frontotemporal Lobar Degeneration, Gene, Gene Deletion, Genetics (clinical)
Abstract: Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD). Most known GRN mutations are null mutations, such as nonsense and frameshift mutations, which create a premature stop codon resulting in loss of function of the progranulin protein. Complete or near-complete genomic GRN deletions have also been found in three families, but heterozygous partial deletions that remove only one or two exons have not been reported to date. In this study, we analysed three unrelated FTLD patients with low plasma progranulin levels but no point GRN mutations by multiplex ligation-dependent probe amplification (MLPA) and quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF). We detected two heterozygous partial GRN deletions in two patients. One deletion removed exon 1 and part of intron 1. The second deletion was complex: it removed 1,410 bp extending from the part of intron 1 to the part of exon 3, with a small 5-bp insertion at the breakpoint junction (c.-7-1121_159delinsGATCA). Our findings illustrate the usefulness of a quantitative analysis in addition to GRN gene sequencing for a comprehensive genetic diagnosis of FTLD, particularly in patients with low plasma progranulin levels.
Published: 2014
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49. Homozygous TREM2 mutation in a family with atypical frontotemporal dementia

Author: Bruno Dubois, Edor Kabashi, Alexis Brice, Paola Caroppo, Rita Guerreiro, Isabelle Le Ber, Anne de Septenville, Agnès Camuzat, Serena Lattante, Kawtar Bouya-Ahmed, Jose Bras, and Philippe Couarch
Subjects: Adult, Male, Aging, Pathology, medicine.medical_specialty, Biology, Corpus callosum, Compound heterozygosity, Settore MED/03 - GENETICA MEDICA, Article, mental disorders, medicine, TREM2, Humans, Dementia, Receptors, Immunologic, Genetic Association Studies, Nasu-Hakola, Membrane Glycoproteins, General Neuroscience, Parkinsonism, Homozygote, Brain, FTD, Frontotemporal lobar degeneration, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Hyperintensity, nervous system diseases, Phenotype, Frontotemporal Dementia, Mutation, Female, Neurology (clinical), Geriatrics and Gerontology, Developmental Biology, Frontotemporal dementia
Abstract: TREM2 mutations were first identified in Nasu-Hakola disease, a rare autosomal recessive disease characterized by recurrent fractures because of bone cysts and presenile dementia. Recently, homozygous and compound heterozygous TREM2 mutations were identified in rare families with frontotemporal lobar degeneration (FTLD) but without bone involvement. We identified a p.Thr66Met heterozygous mutation in a new consanguineous Italian family. Two sibs had early onset autosomal recessive FTLD without severe bone disorders. Atypical signs were present in this family: early parietal and hippocampus involvement, parkinsonism, epilepsy, and corpus callosum thickness on brain magnetic resonance imaging. This study further demonstrates the implication of TREM2 mutations in FTLD phenotypes. It illustrates the variability of bone phenotype and underlines the frequency of atypical signs in TREM2 carriers. This and previous studies evidence that TREM2 mutation screening should be limited to autosomal recessive FTLD with atypical phenotypes characterized by: (1) a very young age at onset (20–50 years); (2) early parietal and hippocampal deficits; (3) the presence of seizures and parkinsonism; (4) suggestive extensive white matter lesions and corpus callosum thickness on brain magnetic resonance imaging.
Published: 2014

50. SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis

Author: Audrey Gabelle, Isabelle Le Ber, Kawtar Bouya-Ahmed, Stéphanie Millecamps, Timothée Lenglet, Agnès Camuzat, Morwena Latouche, Alexis Brice, Didier Hannequin, John Hardy, Mira Didic, Edor Kabashi, Dominique Campion, Jose Bras, Anne de Septenville, Rita Guerreiro, and Gaël Nicolas
Subjects: Oncology, Proband, Male, medicine.medical_specialty, Pathology, Guanine, Neuropsychological Tests, medicine.disease_cause, Article, Cohort Studies, Internal medicine, mental disorders, Sequestosome-1 Protein, Medicine, Missense mutation, Humans, Amyotrophic lateral sclerosis, Adaptor Proteins, Signal Transducing, Aged, Family Health, Tomography, Emission-Computed, Single-Photon, Mutation, business.industry, Amyotrophic Lateral Sclerosis, nutritional and metabolic diseases, Brain, Organotechnetium Compounds, Middle Aged, medicine.disease, Penetrance, Magnetic Resonance Imaging, nervous system diseases, Frontotemporal Dementia, Cohort, Female, Neurology (clinical), France, business, Cohort study, Frontotemporal dementia
Abstract: Importance Mutations in the SQSTM1 gene, coding for p62, are a cause of Paget disease of bone and amyotrophic lateral sclerosis (ALS). Recently, SQSTM1 mutations were confirmed in ALS, and mutations were also identified in 3 patients with frontotemporal dementia (FTD), suggesting a role for SQSTM1 in FTD. Objective To evaluate the exact contribution of SQSTM1 to FTD and FTD with ALS (FTD-ALS) in an independent cohort of patients. Design A SQSTM1 mutation was first identified in a multiplex family with FTD by use of whole-exome sequencing. To evaluate the frequency of SQSTM1 mutations, we sequenced this gene in a cohort of patients with FTD or FTD-ALS, with no mutations in known FTD and ALS genes. Setting Primary care or referral center. Participants An overall cohort of 188 French patients, including 132 probands with FTD and 56 probands with FTD-ALS. Main Outcomes and Measures Frequency of SQSTM1 mutations in patients with FTD or FTD-ALS; description of associated phenotypes. Results We identified 4 heterozygous missense mutations in 4 unrelated families with FTD; only 1 family had clinical symptoms of Paget disease of bone, and only 1 family had clinical symptoms of FTD-ALS, possibly owing to the low penetrance of some of the clinical manifestations. Conclusions and Relevance Although the frequency of the mutations is low in our series (4 of 188 patients [2%]), our results, similar to those already reported, support a direct pathogenic role of p62 in different types of FTD.
Published: 2013

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