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1. Reconstructing B cell lineage trees with minimum spanning tree and genotype abundances

Author

Nika Abdollahi, Lucile Jeusset, Anne de Septenville, Frederic Davi, and Juliana Silva Bernardes

Subjects
B cell receptor repertoire, Lineage Tree, phylogenetics, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract B cell receptor (BCR) genes exposed to an antigen undergo somatic hypermutations and Darwinian antigen selection, generating a large BCR-antibody diversity. This process, known as B cell affinity maturation, increases antibody affinity, forming a specific B cell lineage that includes the unmutated ancestor and mutated variants. In a B cell lineage, cells with a higher antigen affinity will undergo clonal expansion, while those with a lower affinity will not proliferate and probably be eliminated. Therefore, cellular (genotype) abundance provides a valuable perspective on the ongoing evolutionary process. Phylogenetic tree inference is often used to reconstruct B cell lineage trees and represents the evolutionary dynamic of BCR affinity maturation. However, such methods should process B-cell population data derived from experimental sampling that might contain different cellular abundances. There are a few phylogenetic methods for tracing the evolutionary events occurring in B cell lineages; best-performing solutions are time-demanding and restricted to analysing a reduced number of sequences, while time-efficient methods do not consider cellular abundances. We propose ClonalTree, a low-complexity and accurate approach to construct B-cell lineage trees that incorporates genotype abundances into minimum spanning tree (MST) algorithms. Using both simulated and experimental data, we demonstrate that ClonalTree outperforms MST-based algorithms and achieves a comparable performance to a method that explores tree-generating space exhaustively. Furthermore, ClonalTree has a lower running time, being more convenient for building B-cell lineage trees from high-throughput BCR sequencing data, mainly in biomedical applications, where a lower computational time is appreciable. It is hundreds to thousands of times faster than exhaustive approaches, enabling the analysis of a large set of sequences within minutes or seconds and without loss of accuracy. The source code is freely available at github.com/julibinho/ClonalTree.

Published
2023
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2. Reconstructing the evolutionary history of a B cell lineage with minimum spanning tree and genotype abundances

Author

Nika Abdollahi, Lucile Jeusset, Anne de Septenville, Frédéric Davi, and Juliana S. Bernardes

Abstract

B cell receptor (BCR) genes exposed to an antigen undergo somatic hypermutations and Darwinian antigen selection, generating a large BCR-antibody diversity. This process, known as B cell affinity maturation, increases antibody affinity, forming a specific B cell lineage that includes the unmutated ancestor and mutated variants. In a B cell lineage, cells with a higher antigen affinity will undergo clonal expansion, while those with a lower affinity will not proliferate and probably be eliminated. Therefore, cellular (genotype) abundance provides a valuable perspective on the ongoing evolutionary process. Phylogenetic tree inference is often used to reconstruct B cell lineage trees and represents the evolutionary dynamic of BCR affinity maturation. However, such methods should process B cell population data derived from experimental sampling that might contain different cellular abundances. There are a few phylogenetic methods for reconstructing the evolutionary history of B cell lineages; best-performing solutions are time-demanding and restricted to analyzing a reduced number of BCR IGH sequences, while time-efficient methods do not consider cellular abundances. We propose ClonalTree, a low-complexity and accurate approach to reconstruct B cell lineage trees that incorporates genotype abundances into minimum spanning tree (MST) algorithms. Using both simulated and experimental data, we demonstrated that ClonalTree outperforms MST-based algorithms and achieves a similar performance compared to a method that explores tree generating space exhaustively. However, ClonalTree has a lower running time, being more convenient for reconstructing phylogenetic lineage trees from high-throughput BCR sequencing data, mainly in biomedical applications, where a lower computational time is appreciable. It is hundreds to thousands of times faster than exhaustive approaches, enabling the analysis of a large set of sequences within minutes or seconds and without loss of accuracy. The source code is freely available at github.com/julibinho/ClonalTree.

Published
2022

3. Higher-order connections between stereotyped subsets

Author

Andrea Patriarca, Marco Montillo, Niki Stavroyianni, Claudia Haferlach, Lesley-Ann Sutton, Livio Trentin, Franco Fais, Raphael Sandaltzopoulos, Arnon P. Kater, Anton W. Langerak, Marine Armand, Davide Rossi, Diane F. Jelinek, Davide Bagnara, Lydia Scarfò, Andreas Agathangelidis, Krzysztof Giannopoulos, Eugen Tausch, Andrey Sudarikov, Silvio Veronese, Salem H. Alshemmari, B V Biderman, Zadie Davis, Chrysoula Belessi, Lisa Bonello, Achilles Anagnostopoulos, Gerlinde Mitterbauer-Hohendanner, David Oscier, Sofia Kossida, Lone Bredo Pedersen, Paolo Ghia, Csaba Bödör, Christian Brieghel, Andrea Visentin, Véronique Giudicelli, Matthias Ritgen, Panagiotis Panagiotidis, Panagiotis Baliakas, Stephan Stilgenbauer, Ellen J van Gastel, Renee C. Tschumper, Christiane Pott, Frederic Davi, Katerina Gemenetzi, Valentina Guido, Elias Campo, Gianluca Gaidano, Irina Panovska, Sabine Jeromin, Karla Plevová, Kostas Stamatopoulos, Kamila Brázdilová, Maria Karypidou, Alba Navarro, Christof W. Schneider, Theodoros Moysiadis, Larry Mansouri, Darko Antic, Cristina Tresoldi, Constance Baer, Šárka Pospíšilová, Maria Roumelioti, Katrina Vanura, Xiao-Jie Yan, Hana Skuhrová Francová, Richard Rosenquist, Blanca Espinet, Paola Francia di Celle, Monica Facco, Paul Costeas, Michael Hallek, Carsten Utoft Niemann, Teodora Karan-Djurasevic, Manja Meggendorfer, Kirsten Fischer, Aleksandar Dimovski, Letizia Foroni, Marie-Paule Lefranc, Mark Catherwood, Anne de Septenville, Anastasia Chatzidimitriou, Sarah Lawless, Nicholas Chiorazzi, Agathangelidis, Andrea, Chatzidimitriou, Anastasia, Gemenetzi, Katerina, Giudicelli, Veronique, Karypidou, Maria, Plevova, Karla, Davis, Zadie A, Yan, Xiao-Jie, Jeromin, Sabine, Schneider, Christof, Pedersen, Lone Bredo, Tschumper, Renee, Sutton, Lesley A, Baliakas, Panagioti, Scarfò, Lydia, van Gastel, Ellen J, Armand, Marine, Tausch, Eugen, Biderman, Bella, Baer, Constance, Bagnara, Davide, Navarro, Alba, de Septenville, Anne, Guido, Valentina, Mitterbauer-Hohendanner, Gerlinde, Dimovski, Aleksandar, Brieghel, Christian, Lawless, Sarah, Meggendorfer, Manja, Stranska, Kamila, Ritgen, Matthia, Facco, Monica, Tresoldi, Cristina, Visentin, Andrea, Patriarca, Andrea, Catherwood, Mark, Bonello, Lisa, Sudarikov, Andrey, Vanura, Katrina, Roumelioti, Maria, Skuhrova Francova, Hana, Moysiadis, Theodoro, Veronese, Silvio M, Giannopoulos, Krzysztof, Mansouri, Larry, Karan-Djurasevic, Teodora, Sandaltzopoulos, Raphael, Bödör, Csaba, Fais, Franco, Kater, Arnon P, Panovska-Stavridis, Irina, Rossi, Davide, Alshemmari, Salem, Panagiotidis, Panagioti, Costeas, Paul A, Espinet, Blanca, Antic, Darko, Foroni, Letizia, Montillo, Marco, Trentin, Livio, Stavroyianni, Niki, Gaidano, Gianluca, Francia di Celle, Paola, Niemann, Carsten Utoft, Campo, Elía, Anagnostopoulos, Achille, Pott, Christiane, Fischer, Kirsten, Hallek, Michael, Oscier, David Graham, Stilgenbauer, Stephan, Haferlach, Claudia, Jelinek, Diane F, Chiorazzi, Nichola, Pospisilova, Sarka, Lefranc, Marie-Paule, Kossida, Sofia, Langerak, Anton W, Belessi, Chrysoula, Davi, Frederic, Rosenquist, Richard, Ghia, Paolo, Stamatopoulos, Kostas, Experimental Immunology, Clinical Haematology, AII - Cancer immunology, CCA - Cancer biology and immunology, and Immunology

Subjects
Chronic lymphocytic leukemia, Immunology, B-cell receptor, Immunoglobulin Variable Region, Disease, Computational biology, Biology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, hemic and lymphatic diseases, Immunoglobulin, medicine, Humans, Chronic, 030304 developmental biology, Gene Rearrangement, 0303 health sciences, Leukemia, Lymphoid Neoplasia, Repertoire, B-Cell, breakpoint cluster region, Cell Biology, Hematology, Gene rearrangement, Somatic Hypermutation, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphocytic, Stereotypy (non-human), Immunoglobulin Heavy Chains, Somatic Hypermutation, Immunoglobulin, 030220 oncology & carcinogenesis, IGHV@
Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed “satellites,” were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL. Key Points: • In a series of 29 856 CLL patients, the incidence of BcR stereotypy peaked at 41%. • Higher-order relations exist between stereotyped subsets, particularly for those from U-CLL, for which satellite subsets were identified.

Published
2021

4. Immunoglobulin gene analysis in chronic lymphocytic leukemia in the era of next generation sequencing

Author

Frederic Davi, Paul J. Hengeveld, Anastasia Chatzidimitriou, P Martijn Kolijn, Richard Rosenquist, Anne de Septenville, Kostas Stamatopoulos, Lesley-Ann Sutton, Silvia Bonfiglio, Anton W. Langerak, Paolo Ghia, Service d'Hématologie clinique [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), Sorbonne Université (SU), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre for Research and Technology Hellas (CERTH), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), IRCCS Ospedale San Raffaele [Milan, Italy], Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], Immunology, Davi, Frédéric, Langerak, Anton W, de Septenville, Anne Langloi, Kolijn, P Martijn, Hengeveld, Paul J, Chatzidimitriou, Anastasia, Bonfiglio, Silvia, Sutton, Lesley-Ann, Rosenquist, Richard, Ghia, Paolo, and Stamatopoulos, Kostas

Subjects
Immunoglobulin gene, Cancer Research, medicine.medical_specialty, Medical diagnostic, Chronic lymphocytic leukemia, Immunoglobulin Variable Region, Somatic hypermutation, [SDV.CAN]Life Sciences [q-bio]/Cancer, DNA sequencing, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, B-cell receptor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, Medicine, Intensive care medicine, Cancer genetics, Sanger sequencing, Genes, Immunoglobulin, business.industry, High-Throughput Nucleotide Sequencing, Data interpretation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Perspective, symbols, Immunoglobulin Heavy Chains, IGHV@, business, 030215 immunology
Abstract

Twenty years after landmark publications, there is a consensus that the somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene is an important cornerstone for accurate risk stratification and therapeutic decision-making in patients with chronic lymphocytic leukemia (CLL). The IGHV SHM status has traditionally been determined by conventional Sanger sequencing. However, NGS has heralded a new era in medical diagnostics and immunogenetic analysis is following this trend. There is indeed a growing demand for shifting practice and using NGS for IGHV gene SHM assessment, although it is debatable whether it is always justifiable, at least taking into account financial considerations for laboratories with limited resources. Nevertheless, as this analysis impacts on treatment decisions, standardization of both technical aspects, and data interpretation becomes essential. Also, the need for establishing new recommendations and providing dedicated education and training on NGS-based immunogenetics is greater than ever before. Here we address potential and challenges of NGS-based immunogenetics in CLL. We are convinced that this perspective helps the hematological community to better understand the pros and cons of this new technological development for CLL patient management.

Published
2020

5. A multi-objective based clustering for inferring BCR clones from high-throughput B cell repertoire data

Author

Hugues Ripoche, Juliana S Bernardes, Frederic Davi, Nika Abdollahi, and Anne de Septenville

Subjects
Mutation rate, education.field_of_study, Computer science, Repertoire, Population, Somatic hypermutation, Cohesion (computer science), Context (language use), Computational biology, Cluster analysis, education, Selection (genetic algorithm)
Abstract

The adaptive B cell response is driven by the expansion, somatic hypermutation, and selection of B cell clones. A high number of clones in a B cell population indicates a highly diverse repertoire, while clonal size distribution and sequence diversity within clones can be related to antigen’s selective pressure. Identifying clones is fundamental to many repertoire studies, including repertoire comparisons, clonal tracking and statistical analysis. Several methods have been developed to group sequences from high-throughput B cell repertoire data. Current methods use clustering algorithms to group clonally-related sequences based on their similarities or distances. Such approaches create groups by optimizing a single objective that typically minimizes intra-clonal distances. However, optimizing several objective functions can be advantageous and boost the algorithm convergence rate. Here we propose a new method based on multi-objective clustering. Our approach requires V(D)J annotations to obtain the initial clones and iteratively applies two objective functions that optimize cohesion and separation within clones simultaneously. We show that under simulations with varied mutation rates, our method greatly improves clonal grouping as compared to other tools. When applied to experimental repertoires generated from high-throughput sequencing, its clustering results are comparable to the most performing tools. The method based on multi-objective clustering can accurately identify clone members, has fewer parameter settings and presents the lowest running time among existing tools. All these features constitute an attractive option for repertoire analysis, particularly in the clinical context to unravel the mechanisms involved in the development and evolution of B cell malignancies.

Published
2021

6. [Watch out for a second train]

Author

Adélaïde Toutée, Myrto Costopoulos, Clotilde Bravetti, Frederic Davi, Elise Chapiro, Michaël Degaud, Agathe Maillon, Sylvain Choquet, Magali Le Garff-Tavernier, Anne Lavaud, Anne de Septenville, Karim Maloum, and Frédéric Charlotte

Subjects
Male, Pathology, medicine.medical_specialty, Vision, Low, Monoclonal Gammopathy of Undetermined Significance, Flow cytometry, Immunophenotyping, Diagnosis, Differential, Nasal fossae, Medicine, Humans, B cell, Aged, Carcinoma, Transitional Cell, Incidental Findings, Hematologic Tests, medicine.diagnostic_test, business.industry, Eye Neoplasms, Waldenstrom macroglobulinemia, General Medicine, medicine.disease, medicine.anatomical_structure, Immunoglobulin M, Urinary Bladder Neoplasms, Lymphoma, Large B-Cell, Diffuse, Urothelium, Waldenstrom Macroglobulinemia, business, Diffuse large B-cell lymphoma
Abstract

We report the case of a man with a primary diagnosis of Waldenstrom macroglobulinemia. He secondarily presented a diffuse large B cell lymphoma (DLBCL) located in the nasal fossae, which relapsed later in the eye. The diagnosis of these two malignancies is based on a multidisciplinary biological approach using new sensitive and specific techniques. These techniques revealed that the two diseases harbor different B cell clones, indicating a distinct origin. This observation highlights the importance of targeted biological techniques for the diagnosis of these two rare hemopathies. It also shows that it is possible to prove the independent nature of the two tumor clones, thus allowing optimized therapeutic management.

Published
2020

7. Reply: Is CHCHD10 Pro34Ser pathogenic for frontotemporal dementia and amyotrophic lateral sclerosis?

Author

Samira Ait-El-Mkadem, Alexis Brice, Anne de Septenville, Hiromi Sesaki, Valérie Serre, Annabelle Chaussenot, David Moore, Patrick Yu-Wai-Man, Cécile Rouzier, Charlotte Cochaud, Yusuke Kageyama, Karine Nguyen, Emmanuelle C. Genin, Gaëlle Augé, Isabelle Le Ber, Véronique Paquis-Flucklinger, Annie Verschueren, Konstantina Fragaki, Sandra Lacas-Gervais, Jean Pouget, Laetitia Berg-Alonso, Sylvie Bannwarth, Françoise Lespinasse, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Medical Genetics, National Centre for Mitochondrial Diseases-Nice Teaching Hospital, Joint Centre for Applied Electron Microscopy, Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Department of Cell Biology, Baltimore, Johns Hopkins University School of Medicine, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Wellcome Trust Centre for Mitochondrial Research, Newcastle University [Newcastle]-International Centre for Life-Institute of Genetic Medicine, Neuro-Oncologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Pitié-Salpêtrière [APHP], 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 [APHP]-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE)-Marseille Teaching Hospital, Newcastle Eye Centre, Royal Victoria Infirmary, Association Française contre les Myopathies (AFM), Fondation pour la Recherche Médicale (FRM), National Institutes of Health (GM089853), program ‘Investissements d’avenir’ ANR-10-IAIHU-06, ‘The Programme Hospitalier de Recherche Clinique’, 7th framework program of the European Union (FP7, E12009DD, Neuromics), Clinician Scientist Fellowship Award (G1002570) from the Medical Research Council (UK), Fight for Sight (UK), UK National Institute of Health Research (NIHR) as part of the Rare Diseases Translational Research Collaboration, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), CHU Pitié-Salpêtrière [AP-HP], 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), 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
Male, medicine.medical_specialty, Mitochondrial Diseases, Amyotrophic Lateral Sclerosis, medicine.disease, Pathogenicity, Dermatology, DNA, Mitochondrial, 3. Good health, Mitochondria, Mitochondrial Proteins, Mitochondrial myopathy, Frontotemporal Dementia, medicine, Dementia, Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Neurology (clinical), Amyotrophic lateral sclerosis, Psychology, Motor neuropathy, Neuroscience, ComputingMilieux_MISCELLANEOUS, Frontotemporal dementia
Abstract

Sir, We and others have identified different CHCHD10 mutations responsible for mitochondrial DNA instability disorder, early-onset mitochondrial myopathy, frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) clinical spectrum and late-onset spinal motor neuropathy (SMAJ) (Bannwarth et al. , 2014, 2015; Chaussenot et al. , 2014; Johnson et al. , 2014; Muller et al. , 2014; Ajroud-Driss et al. , 2015; Kurzwelly et al. , 2015; Penttila et al. , 2015; Ronchi et al. , 2015). The letter from Dobston-Stone et al. , (2015) asks the question about the pathogenicity of the Pro34Ser variant that was previously identified by our group in two unrelated French patients with FTD-ALS (Chaussenot et al. , 2014) and by Ronchi et al. (2015) in one Italian patient with ALS. We read with interest this study reporting the screening of CHCHD10 in several Australian cohorts that leads to the identification of the Pro34Ser variant in (i) two unrelated patients with familial FTD; (ii) five individuals with early-onset dementia among …

Published
2015

8. 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

9. Reply: CHCHD10 mutations in Italian patients with sporadic amyotrophic lateral sclerosis

Author

Françoise Lespinasse, Karine Nguyen, Patrick Yu-Wai-Man, Alexis Brice, Véronique Paquis-Flucklinger, David Moore, Laetitia Berg-Alonso, Sandra Lacas-Gervais, Anne de Septenville, Cécile Rouzier, Charlotte Cochaud, Valérie Serre, Annabelle Chaussenot, Yusuke Kageyama, Hiromi Sesaki, Emmanuelle C. Genin, Samira Ait-El-Mkadem, Jean Pouget, Sylvie Bannwarth, Gaëlle Augé, Isabelle Le Ber, Annie Verschueren, Konstantina Fragaki, Service de génétique médicale, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Commun de Microscopie Appliquée (CCMA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Department of Cell Biology, Baltimore, Johns Hopkins University School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Wellcome Trust Centre for Mitochondrial Research, Newcastle University [Newcastle]-International Centre for Life-Institute of Genetic Medicine, Neuro-Oncologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), 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), Department of Medical Genetics, National Centre for Mitochondrial Diseases-Nice Teaching Hospital, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, Hôpital de la Timone [CHU - APHM] (TIMONE), 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), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), 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), 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)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and 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)

Subjects
Oncology, Male, medicine.medical_specialty, Pathology, Mitochondrial Diseases, [SDV]Life Sciences [q-bio], Disease, DNA, Mitochondrial, Mitochondrial Proteins, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Missense mutation, Humans, Amyotrophic lateral sclerosis, Letters to the Editor, Mitochondrial protein, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, Amyotrophic Lateral Sclerosis, medicine.disease, Mitochondria, Frontotemporal Dementia, Cohort, Mutation (genetic algorithm), Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Sir, The work from Giacomo Comi’s group in Milan confirms that CHCHD10 is associated with motor neuron disease (Ronchi et al. , 2015). Firstly, this group identified two individuals who carried a CHCHD10 mutation among a cohort of 218 Italian patients with sporadic amyotrophic lateral sclerosis (ALS) (1.4%). A female, who developed bulbar ALS at 75 years of age, carried the p.Pro34Ser mutation that we previouly identified in two unrelated frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) patients (Chaussenot et al. , 2014). A novel missense mutation (p.Pro80Leu) was also found in two unrelated males who developed the disease at 25 and 59 years of age, respectively. After the identification of CHCHD10 mutations in FTD-ALS and familial pure ALS cohorts, this novel study supports the involvement of this gene in sporadic ALS (Chaussenot et al. , 2014; Johnson et al. , 2014; Muller et al. , 2014; Ronchi …

Published
2015

10. 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

11. Reply: Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis

Author

Annabelle Chaussenot, Karine Nguyen, Patrick Yu-Wai-Man, David Moore, Emmanuelle C. Genin, Cécile Rouzier, Véronique Paquis-Flucklinger, Charlotte Cochaud, Françoise Lespinasse, Sandra Lacas-Gervais, Alexis Brice, Gaëlle Augé, Isabelle Le Ber, Yusuke Kageyama, Anne de Septenville, Samira Ait-El-Mkadem, Laetitia Berg-Alonso, Annie Verschueren, Konstantina Fragaki, Jean Pouget, Hiromi Sesaki, Sylvie Bannwarth, Valérie Serre, Service de génétique médicale, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Commun de Microscopie Appliquée (CCMA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Department of Cell Biology, Baltimore, Johns Hopkins University School of Medicine, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Wellcome Trust Centre for Mitochondrial Research, Newcastle University [Newcastle]-International Centre for Life-Institute of Genetic Medicine, Neuro-Oncologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), 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), Department of Medical Genetics, National Centre for Mitochondrial Diseases-Nice Teaching Hospital, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, Hôpital de la Timone [CHU - APHM] (TIMONE), 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), 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 Génomique Fonctionnelle (GMGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), 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), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS)-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 National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and 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)

Subjects
Male, Mitochondrial Diseases, [SDV]Life Sciences [q-bio], Biology, DNA, Mitochondrial, DNA sequencing, Mitochondrial Proteins, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, medicine, Humans, Amyotrophic lateral sclerosis, Letters to the Editor, Gene, Exome sequencing, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Sanger sequencing, Genetics, 0303 health sciences, Haplotype, Amyotrophic Lateral Sclerosis, medicine.disease, 3. Good health, Mitochondria, Frontotemporal Dementia, Mutation (genetic algorithm), symbols, Female, Neurology (clinical), 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Sir, The letter to the editor from Johnson and colleagues provides new information confirming that mitochondrondrial dysfunction could be an important player contributing to the aetiology of amyotrophic lateral sclerosis (ALS) through the involvement of the CHCHD10 gene. We first identified four patients harbouring a mutation in this gene among a total population of 116 individuals presenting with ALS-frontotemporal dementia (FTD) (Bannwarth et al., 2014; Chaussenot et al., 2014). Then, whole exome sequencing in 102 German and 26 Nordic patients with pure ALS led to the identification of three families in which a CHCHD10 mutation segregates with the disease (Mueller et al., 2014). In their study, Johnson and colleagues showed that CHCHD10 is responsible for five novel cases among a cohort of 85 patients with familial ALS. All these data confirm the clinical, molecular and mechanistic continuum between FTD and ALS and raise the intriguing prospect of an underlying mitochondrial basis for this group of disorders. Regarding CHCHD10 mutations, we agree with Johnson and colleagues that their identification by exome sequencing is difficult due to their location in a GC-rich region responsible for a low coverage. Genome sequencing can be an alternative approach but CHCHD10 sequencing using the Sanger method must be systematically performed when exome sequencing is not conclusive. Each CHCHD10 mutation that we identified in ALS-FTD patients was found twice. The p.Ser59Leu mutation is located in the hydrophobic N-terminal α helix of CHCHD10 while the p.Pro34Ser is located in the non-structured N-terminal region (Bannwarth et al., 2014; Chaussenot et al., 2014). The deleterious variants found in patients with pure ALS are different but also recurrent. The p.Arg15Leu mutation was identified in five of eight cases and all patients reported by Johnson and colleagues, who carried this variant, shared a 6.2 Mb haplotype across the gene. Only the Gly66Val mutation was found once until now. The p.Arg15Leu is located in the non-structured N-terminal region whereas the p.Gly66Val variant is located in the N-terminal α helix. In conclusion, CHCHD10 mutations located in the non-structured N-terminal region or in the α helix are responsible for both ALS and ALS-FTD phenotypes. No deleterious variant has been found in the CHCH domain near the C-terminal region. The large majority of CHCHD10 mutations that were identified are recurrent, including the p.Arg15Leu variant that was found in five of eight cases with pure ALS. Further studies in larger cohorts are needed, but initial results involving French, German, Finnish, North American, Israeli, Italian and Canadian populations suggest that the frequency of CHCHD10 mutations must be between 3 and 5% in the ALS and ALS-FTD clinical spectrum (Bannwarth et al., 2014; Chaussenot et al., 2014; Mueller et al., 2014).

Published
2014

12. Reply: Are CHCHD10 mutations indeed associated with familial amyotrophic lateral sclerosis?

Author

Sylvie Bannwarth, Samira Ait-El-Mkadem, Annabelle Chaussenot, Emmanuelle C. Genin, Sandra Lacas-Gervais, Konstantina Fragaki, Laetitia Berg-Alonso, Yusuke Kageyama, Valérie Serre, David Moore, Annie Verschueren, Cécile Rouzier, Isabelle Le Ber, Gaëlle Augé, Charlotte Cochaud, Françoise Lespinasse, Karine N’Guyen, Anne de Septenville, Alexis Brice, Patrick Yu-Wai-Man, Hiromi Sesaki, Jean Pouget, Véronique Paquis-Flucklinger, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Department of Medical Genetics, National Centre for Mitochondrial Diseases-Nice Teaching Hospital, Joint Centre for Applied Electron Microscopy, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Department of Cell Biology, Baltimore, Johns Hopkins University School of Medicine, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Newcastle University [Newcastle], Wellcome Trust Centre for Mitochondrial Research, Newcastle University [Newcastle]-International Centre for Life-Institute of Genetic Medicine, Neuro-Oncologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), 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), Hôpital de la Timone [CHU - APHM] (TIMONE)-Marseille Teaching Hospital, 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), Newcastle Eye Centre, Royal Victoria Infirmary, Association Française contre les Myopathies (AFM), Fondation pour la Recherche Médicale (FRM), National Institutes of Health (GM089853), program ‘Investissements d’avenir’ ANR-10-IAIHU-06, Programme Hospitalier de Recherche Clinique, 7th framework program of the European Union (FP7, E12009DD, Neuromics), Clinician Scientist Fellowship Award (G1002570), Université Nice Sophia Antipolis (... - 2019) (UNS), 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), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Ataxia, Mitochondrial Diseases, Hearing loss, Pedigree chart, Disease, DNA, Mitochondrial, Mitochondrial Proteins, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Amyotrophic lateral sclerosis, Myopathy, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, Amyotrophic Lateral Sclerosis, medicine.disease, Mitochondria, Frontotemporal Dementia, Mutation (genetic algorithm), Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), medicine.symptom, Psychology, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Sir, A recent study by Bannwarth et al. (2014) in Brain identified a novel mutation (c.176C > T; p.Ser59Leu) in the CHCHD10 gene that segregates in a family presenting with ataxia, myopathy, hearing loss as well as motor neuron disease and frontotemporal dementia (FTD). Furthermore they identified a second family with ALS/FTD harbouring the identical mutation making this a gene of interest in the pathogenesis of ALS/FTD. For this reason we read with great interest the letter by Muller et al. (2014) that describes the identification of two novel variants in CHCHD10 in three pedigrees with familial amyotrophic lateral sclerosis (ALS). The authors state that their findings provide strong support for CHCHD10 being a novel ALS gene. Although their findings are highly interesting and their conclusion is appealing, we feel obliged to make several remarks concerning the genetic evidence provided to support this statement. The definition of genetic evidence, driven by the problem of non-replicating findings, is a matter of concern over the past years and has led to multiple consensus definitions for different study designs (reviewed by Pulit et al. , 2014). A landmark paper published nearly 20 years ago defined segregation of the gene with the studied phenotype within a pedigree resulting in a LOD score ≥ 3 as robust genetic evidence (Lander and Kruglyak, 1995). For …

Published
2014

13. 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

14. Reply: Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease

Author

Sandra Lacas-Gervais, Karine Nguyen, Véronique Paquis-Flucklinger, Samira Ait-El-Mkadem, Emmanuelle C. Genin, Annabelle Chaussenot, Sylvie Bannwarth, Alexis Brice, Valérie Serre, Annie Verschueren, Konstantina Fragaki, Gaëlle Augé, Laetitia Berg-Alonso, Patrick Yu-Wai-Man, Isabelle Le Ber, Yusuke Kageyama, Anne de Septenville, David Moore, Jean Pouget, Françoise Lespinasse, Hiromi Sesaki, Cécile Rouzier, Charlotte Cochaud, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Department of Medical Genetics, National Centre for Mitochondrial Diseases-Nice Teaching Hospital, Joint Centre for Applied Electron Microscopy, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Department of Cell Biology, Baltimore, Johns Hopkins University School of Medicine, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Wellcome Trust Centre for Mitochondrial Research, Newcastle University [Newcastle]-International Centre for Life-Institute of Genetic Medicine, Neuro-Oncologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), 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], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Timone [CHU - APHM] (TIMONE)-Marseille Teaching Hospital, Newcastle Eye Centre, Royal Victoria Infirmary, Association Française contre les Myopathies (AFM), Fondation pour la Recherche Médicale (FRM), National Institutes of Health (GM089853), program 'Investissements d'avenir' ANR-10-IAIHU-06, 'The Programme Hospitalier de Recherche Clinique', 7th framework program of the European Union (FP7, E12009DD, Neuromics), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), and CHU Pitié-Salpêtrière [APHP]

Subjects
Male, Mitochondrial DNA, Mitochondrial Diseases, Biology, medicine.disease_cause, DNA, Mitochondrial, Mitochondrial Proteins, Mitochondrial myopathy, medicine, Humans, Amyotrophic lateral sclerosis, Cognitive decline, Letters to the Editor, Gene, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Genetics, Mutation, Cerebellar ataxia, Amyotrophic Lateral Sclerosis, medicine.disease, Mitochondria, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Frontotemporal Dementia, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), medicine.symptom
Abstract

Sir, In a recent publication in Brain , we described a novel heterozygous CHCHD10 mutation (c.176C>T; p.Ser59Leu) in a large French family with a late-onset phenotype including cognitive decline resembling frontotemporal dementia (FTD), motor neuron disease, cerebellar ataxia and mitochondrial myopathy with multiple mtDNA deletions (Bannwarth et al. , 2014). We found the same pathogenic mutation in one family in a cohort of 21 families with pathologically proven FTD-ALS (amyotrophic lateral sclerosis). We also showed that the CHCHD10 gene encodes a mitochondrial protein located in the intermembrane space, and that it is likely involved in the maintenance of cristae junctions and mtDNA stability. This work led to the identification of a novel gene responsible for FTD-ALS and the intriguing realization that mitochondrial dysfunction could be an important pathophysiological player contributing to the aetiology of these diseases. The letter from Muller et al. (2014) contains important information that confirms the involvement of the CHCHD10 gene in ALS. They performed whole exome sequencing in 102 German and 26 Nordic ALS patients. By screening CHCHD10 , they identified two novel heteozygous variants: c.44G>T (p.Arg15Leu) in two German families and c.197G>T (p.Gly66Val) in one Finnish family. Although it was not possible to confirm the deleterious nature of these variants through segregation analysis due to the limited number of DNA samples available per family, their absence in public and in-house SNP databases, and in ethnically matched controls in addition to the evolutionary conservation of the corresponding amino acid residues are all in favour …

Published
2014

15. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement

Author

Sylvie Bannwarth, Annie Verschueren, Konstantina Fragaki, Valérie Serre, Emmanuelle C. Genin, David Moore, Patrick Yu-Wai-Man, Alexis Brice, Annabelle Chaussenot, Anne de Septenville, Françoise Lespinasse, Hiromi Sesaki, Laetitia Berg-Alonso, Gaëlle Augé, Isabelle Le Ber, Yusuke Kageyama, Cécile Rouzier, Charlotte Cochaud, Sandra Lacas-Gervais, Karine Nguyen, Véronique Paquis-Flucklinger, Samira Ait-El-Mkadem, Jean Pouget, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Department of Medical Genetics, National Centre for Mitochondrial Diseases-Nice Teaching Hospital, Joint Centre for Applied Electron Microscopy, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Department of Cell Biology, Baltimore, Johns Hopkins University School of Medicine, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Wellcome Trust Centre for Mitochondrial Research, Newcastle University [Newcastle]-International Centre for Life-Institute of Genetic Medicine, Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de 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), Hôpital de la Timone [CHU - APHM] (TIMONE)-Marseille Teaching Hospital, Association Française contre les Myopathies (AFM), Fondation pour la Recherche Médicale (FRM), National Institutes of Health (GM089853), Programme Hospitalier de Recherche Clinique, Clinician Scientist Fellowship Award (G1002570), Medical Research Council (UK), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), CHU Pitié-Salpêtrière [APHP], Yu Wai Man, Patrick [0000-0001-7847-9320], Apollo - University of Cambridge Repository, and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Pathology, medicine.medical_specialty, Mitochondrial DNA, Mitochondrial Diseases, Mitochondrial disease, Mutation, Missense, Mitochondrion, Biology, DNA, Mitochondrial, Mitochondrial Proteins, mitochondrial disorder, medicine, mitochondrial DNA instability, Missense mutation, Humans, Exome, Amyotrophic lateral sclerosis, Age of Onset, Alleles, Aged, Multiple mitochondrial DNA deletions, Amyotrophic Lateral Sclerosis, Middle Aged, medicine.disease, 3. Good health, Mitochondria, Pedigree, Phenotype, CHCHD10, mitochondrial fusion, Frontotemporal Dementia, Female, FTD-ALS, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Frontotemporal dementia, HeLa Cells
Abstract

International audience; Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes.

Published
2014

16. 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

17. 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

18. 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

19. 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

20. TREM2 mutations are rare in a French cohort of patients with frontotemporal dementia

Author

Agnès Camuzat, Serena Lattante, Inge Van Bortel, Sarah Dayan, Alexis Brice, Chloé Godard, Isabelle Le Ber, Anne de Septenville, Sorana Ciura, and Edor Kabashi

Subjects
Aging, Disease, medicine.disease_cause, Settore MED/03 - GENETICA MEDICA, White People, Cohort Studies, Mutation Rate, Polymorphism (computer science), mental disorders, Humans, Medicine, Exome, Receptors, Immunologic, Exome sequencing, Genetics, Mutation, Membrane Glycoproteins, business.industry, TREM2, General Neuroscience, trem2, nutritional and metabolic diseases, Middle Aged, medicine.disease, Phenotype, nervous system diseases, Frontotemporal Dementia, Cohort, France, Neurology (clinical), Geriatrics and Gerontology, business, Developmental Biology, Frontotemporal dementia
Abstract

Homozygous mutations in TREM2 have been recently identified by exome sequencing in families presenting with frontotemporal dementia (FTD)–like phenotype. No study has evaluated the exact frequency of TREM2 mutations in cohorts of FTD patients so far. We sequenced TREM2 in 175 patients with pure FTD, mostly French, to test whether mutations could be implicated in the pathogenesis of the disease. No disease-causing mutation was identified in 175 individuals from the French cohort of FTD patients. We did not identify the polymorphism p.R47H (rs75932628), strongly associated with an increased risk of developing Alzheimer's disease. We conclude that TREM2 mutations are extremely rare in patients with pure FTD, although further investigation in larger populations is needed.

Published
2013

21. Reply: High prevalence ofCHCHD10mutations in patients with frontotemporal dementia from China: Table 1

Author

Patrick Yu-Wai-Man, Alexis Brice, Karine Nguyen, Véronique Paquis-Flucklinger, Sandra Lacas-Gervais, Emmanuelle C. Genin, Anne de Septenville, Jean Pouget, David Moore, Annabelle Chaussenot, Cécile Rouzier, Charlotte Cochaud, Annie Verschueren, Konstantina Fragaki, Françoise Lespinasse, Yusuke Kageyama, Laetitia Berg-Alonso, Gaëlle Augé, Isabelle Le Ber, Sylvie Bannwarth, Hiromi Sesaki, Valérie Serre, and Samira Ait-El-Mkadem

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, High prevalence, business.industry, Disease, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Mitochondrial myopathy, Internal medicine, mental disorders, medicine, In patient, Neurology (clinical), Cognitive decline, Amyotrophic lateral sclerosis, business, Neuroscience, Motor neuropathy, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Sir, In 2014, we provided a genetic basis to support the conclusion that mitochondrial dysfunction can have a causative effect in motor neuron degeneration. We reported a large family with a mitochondrial myopathy associated with motor neuron disease and cognitive decline looking like frontotemporal dementia (FTD). Since the identification of the p.Ser59Leu mutation in the CHCHD10 gene in this family, more than a dozen publications have reported CHCHD10 variants in patient cohorts from different geographic origins. CHCHD10 -related clinical spectrum is continuously expanding and includes FTD, familial or sporadic amyotrophic lateral sclerosis (ALS), FTD-ALS, late-onset spinal motor neuropathy and Charcot-Marie-Tooth disease type 2 (Bannwarth et al. , 2014; Chaussenot et al. , 2014; Johnson et al. , 2014; Muller et al. , 2014; Auranen et al. , 2015; Chio et al. , 2015; Dols-Icardo et al. , 2015; Kurzwelly et al. , 2015; Penttila et al. , 2015; Ronchi et al. , 2015; Zhang et al. , 2015). We read with interest the Letter to the Editor from Bin et al. (2015) suggesting that CHCHD10 is the most important gene linked to FTD in the Chinese population. Among a cohort of 165 patients with ALS and 65 patients with FTD, they identified …

Published
2015

22. Reply: A distinct clinical phenotype in a German kindred with motor neuron disease carrying aCHCHD10mutation: Table 1

Author

Françoise Lespinasse, Cécile Rouzier, Charlotte Cochaud, Emmanuelle C. Genin, Hiromi Sesaki, Patrick Yu-Wai-Man, Annie Verschueren, Konstantina Fragaki, Samira Ait-El-Mkadem, Anne de Septenville, Sylvie Bannwarth, Yusuke Kageyama, Gaëlle Augé, Isabelle Le Ber, Alexis Brice, Valérie Serre, David Moore, Karine Nguyen, Laetitia Berg-Alonso, Véronique Paquis-Flucklinger, Sandra Lacas-Gervais, Jean Pouget, and Annabelle Chaussenot

Subjects
Genetics, 0303 health sciences, Mutation, Disease, Motor neuron, Biology, medicine.disease_cause, medicine.disease, language.human_language, German, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, medicine, language, Neurology (clinical), Amyotrophic lateral sclerosis, Clinical phenotype, 030217 neurology & neurosurgery, 030304 developmental biology, Frontotemporal dementia, Heterozygous mutation
Abstract

Sir, In a relatively short period of time, an increasing body of evidence has accumulated confirming the primary role of mitochondrial dysfunction in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) clinical spectrum through the involvement of CHCHD10 both in familial and sporadic cases (Bannwarth et al. , 2014; Chaussenot et al. , 2014; Johnson et al. , 2014; Muller et al. , 2014; Ronchi et al. , 2015). In a new Letter to the Editor submitted to Brain , Kurzwelly et al. (2015) report another large German family with a history of autosomal dominant pure ALS. Affected individuals harboured the c.44G > T (p.Arg15Leu) heterozygous mutation in CHCHD10 , which has been previously identified in five of six families with pure ALS associated with mutations in this gene (two from Germany and three from the USA) (Johnson et al. , 2014; Muller et al. , 2014). The main characteristics of patients reported with CHCHD10 mutations and FTD-ALS clinical spectrum have been summarized in Table 1. The additional German family reported by Kurzwelly et al. highlights several important clinical points that …

Published
2015

23. Genetic analysis of matrin 3 gene in French amyotrophic lateral sclerosis patients and frontotemporal lobar degeneration with amyotrophic lateral sclerosis patients

Author

Mélanie Albert, Agnès Camuzat, Mailys Daniau, Daniela Galimberti, Stéphanie Millecamps, Eric LeGuern, Anne de Septenville, Yannick Marie, Alexis Brice, Isabelle Le Ber, and Elisa Teyssou

Subjects
Aging, Pathology, medicine.medical_specialty, Disease, Genetic analysis, Cohort Studies, Pathogenesis, Nuclear Matrix-Associated Proteins, mental disorders, medicine, Humans, Genetic Predisposition to Disease, Amyotrophic lateral sclerosis, Gene, Exome, Genetic Association Studies, business.industry, General Neuroscience, Amyotrophic Lateral Sclerosis, RNA-Binding Proteins, nutritional and metabolic diseases, Exons, Frontotemporal lobar degeneration, medicine.disease, nervous system diseases, Mutation, France, Neurology (clinical), Frontotemporal Lobar Degeneration, Geriatrics and Gerontology, business, Developmental Biology, Frontotemporal dementia
Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are adult-onset neurodegenerative diseases with overlapping clinical characteristics. They share common genetic causes and pathologic hallmarks such as TDP-43 neuronal accumulations. Recently, exome analysis identified mutations in matrin 3 (MATR3) gene in patients with familial ALS, suggesting a role for this gene in the pathogenesis of the disease. MATR3 is a nuclear matrix protein with DNA and RNA binding domains that interacts with TDP-43. To confirm the contribution of MATR3 to ALS, we studied a French cohort of 153 familial ALS or ALS/FTLD patients, without finding any variant. We conclude that mutations in MATR3 are rare in French familial ALS and ALS with FTLD patients.

Published
2014

24. Screening of CHCHD10 in a French cohort confirms the involvement of this gene in frontotemporal dementia with amyotrophic lateral sclerosis patients

Author

Alexis Brice, Agnès Camuzat, Sylvie Bannwarth, Emmanuelle C. Genin, Annabelle Chaussenot, Jean Pouget, Gaëlle Augé, Isabelle Le Ber, Valérie Serre, Anne de Septenville, Véronique Paquis-Flucklinger, and Samira Ait-El-Mkadem

Subjects
Male, Proband, Aging, Mitochondrial DNA, Pathology, medicine.medical_specialty, Mitochondrial disease, Genomic Instability, Cohort Studies, Mitochondrial Proteins, mental disorders, medicine, Humans, Amyotrophic lateral sclerosis, Myopathy, Genetic Association Studies, Aged, Cerebellar ataxia, business.industry, General Neuroscience, Amyotrophic Lateral Sclerosis, nutritional and metabolic diseases, Middle Aged, medicine.disease, Phenotype, Mitochondria, nervous system diseases, Frontotemporal Dementia, Mutation, Female, France, Neurology (clinical), Geriatrics and Gerontology, medicine.symptom, business, Developmental Biology, Frontotemporal dementia
Abstract

Mutations in the CHCHD10 gene have been recently identified in a large family with a complex phenotype variably associating frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS), cerebellar ataxia, myopathy, and hearing impairment. CHCHD10 encodes a protein located in the mitochondrial intermembrane space and is likely involved in mitochondrial genome stability and maintenance of cristae junctions. However, the exact contribution of CHCHD10 in FTD and ALS diseases spectrum remains unknown. In this study, we evaluated the frequency of CHCHD10 mutations in 115 patients with FTD and FTD-ALS phenotypes. We identified 2 heterozygous variants in 3 unrelated probands presenting FTD and ALS, characterized by early and predominant bulbar symptoms. This study demonstrates the implication of CHCHD10 in FTD and ALS spectrum. Although the frequency of mutations is low in this series (2.6%), our work suggests that CHCHD10 mutations should be searched particularly when bulbar symptoms are present at onset.

Published
2014

25. DCTN1Mutation Analysis in Families With Progressive Supranuclear Palsy–Like Phenotypes

Author

Isabelle Le Ber, Richard Levy, Vanessa Mourlon, Mathilde Sauvée, Fabienne Clot, Sophie Rivaud-Péchoux, Anne de Septenville, Thibaud Lebouvier, Alexis Brice, A. M. Bonnet, Martine Vercelletto, Agnès Camuzat, Claire Boutoleau-Bretonnière, and Paola Caroppo

Subjects
Adult, Male, DNA Mutational Analysis, Biology, TARDBP, Progressive supranuclear palsy, C9orf72, medicine, Humans, Point Mutation, Dementia, Amyotrophic lateral sclerosis, Dystonia, Genetics, Parkinsonism, Dynactin Complex, Middle Aged, medicine.disease, eye diseases, Pedigree, Phenotype, Female, Supranuclear Palsy, Progressive, Neurology (clinical), Microtubule-Associated Proteins, Frontotemporal dementia
Abstract

Importance Progressive supranuclear palsy (PSP) is usually sporadic, but few pedigrees with familial clustering of PSP-like phenotypes have been described. Occasionally, MAPT, C9ORF72 , and TARDBP mutations have been identified. Objective To analyze the DCTN1 gene in 19 families with a clinical phenotype of PSP (PSP-like phenotype). Design, Setting, and Participants Sequencing of the DCTN1 gene in familial forms of PSP at a referral center among 21 patients with familial PSP-like phenotypes. In addition, 8 patients and relatives from a family carrying a DCTN1 mutation were evaluated. Main Outcomes and Measures Identification of the DCTN1 mutation and clinical description of DCTN1 mutation carriers. Results We identified a DCTN1 mutation in a large family characterized by high intrafamilial clinical phenotype variability. Two patients had PSP-like phenotypes with dystonia, vertical gaze slowness, dysexecutive syndrome, predominant axial rigidity, and midbrain atrophy on brain magnetic resonance imaging. The other patients manifested Perry syndrome, isolated parkinsonism, or a predominant behavioral variant of frontotemporal dementia. Conclusions and Relevance Mutations of the DCTN1 gene have been previously associated with amyotrophic lateral sclerosis and with Perry syndrome, a rare autosomal dominant disorder characterized by weight loss, parkinsonism, central hypoventilation, and psychiatric disturbances. Our study demonstrates that DCTN1 mutations should be searched for in patients with clinical PSP-like phenotypes and a behavioral variant of frontotemporal dementia, especially when a familial history of dementia, psychiatric disturbances, associated parkinsonism, or an autosomal dominant disorder is present.

Published
2014

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