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1. Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Author

Granit, Volkan, Steele, Julie, Levy, Wendy, Paredes, Maria Elena, Hernandez, Jessica, Bilsker, Martin, Szacka, Katarzyna, Ronert, Adam, Jablońska, Dorota, Łuczak, Alina Zuzanna, Chaverri, Delia, Janse van Mantgem, Mark R, Bunte, Tommy M, Broere, Bianca, de Fockert, Arianne, Sanchez-Tejerina, Daniel, Landabaso, Carmen, Calvo, Andrea, Moglia, Cristina, Manera, Umberto, Canosa, Antonio, Vasta, Rosario, Salamone, Paolina, Fuda, Giuseppe, DeMarco, Giovanni, Casale, Federico, ME Forsberg, Karin, Winroth, Ivar, Almgren Stenberg, Erica, Holmgren, Monica, Amador, Maria del Mar, Lenglet, Timothee, Querin, Giorgia, Coudoin, Sylvie, Pavlakis, Pantelis, Holzberg, Shara, Sideri, Riccardo, Marinou, Kalliopi, Czarnecki, Maciej, Ługiewicz, Renata, Biel-Czarnecka, Marta, Boczkowska, Marcelina, Schotte, Caroline, Vynckier, Jan, Van Daele, Sien, Claeys, Thomas, Delmotte, Koen, Swinnen, Bart, Serrien, Anouk, D'Hondt, Ann, Lamaire, Nikita, Debien, Elisa, Jones, Sarah, Vachon, Chris, Grogan, James, Solorzano, Guillermo, Crowell, Allison, Rakocevic, Goran, Wagoner, Mary, Alma, Osmanovic, Flavia, Wiehler, Sonja, Körner, Olivia, Schreiber-Katz, Camilla, Wohnrade, Anastasia, Sarikidi, Carola, Kassebaum, Chantal, Fischer, Adamo, Ashley, Turcotte, Nicole, Duncan, Jessie, Turner, Ivone, Elman, Lauren, Massie, Rami, Berube, Maxime, Saunders, Natalie, Salmon, Kristiana, Foucher, Juliette, Agessandro, Abrahao, Shirley, Pham, Jahan, Mookshah, Phung, Liane, Statland, Jeffrey, Jawdat, Omar, Dimachkie, Mazen, Pasnoor, Mamatha, Farmakidis, Constantine, Heim, Andrew, Lillig, Katie, Lackey, Alyssa, Weber, Markus, Kurz, Martina, Levine, Todd, Benatar, Michael, Hansen, Thomas, Rom, Dror, Geist, Marie A, Blaettler, Thomas, Camu, William, Kuzma-Kozakiewicz, Magdalena, van den Berg, Leonard H, Morales, Raul Juntas, Chio, Adriano, Andersen, Peter M, Pradat, Pierre-Francois, Lange, Dale, Van Damme, Philip, Mora, Gabriele, Grudniak, Mariusz, Elliott, Matthew, Petri, Susanne, Olney, Nicholas, Ladha, Shafeeq, Goyal, Namita A, Meyer, Thomas, Hanna, Michael G, Quinn, Colin, Genge, Angela, Zinman, Lorne, Jabari, Duaa, Shoesmith, Christen, Ludolph, Albert C, Neuwirth, Christoph, Nations, Sharon, Shefner, Jeremy M, Turner, Martin R, Wuu, Joanne, Bennett, Richard, Dang, Hoang, and Sundgreen, Claus

Published
2024
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3. HeterozygousSPTLC1p.Leu39del is a major cause of slow-progressing juvenile ALS

Author

Guissart, Claire, primary, De la Cruz, Elisa, additional, Flabeau, Olivier, additional, Grapperon, Aude-Marie, additional, Corazza, Giovanni, additional, Junilhon, Lucie, additional, Delmas, Jean-Charles, additional, Millecamps, Stéphanie, additional, Polge, Anne, additional, Amador, Maria del Mar, additional, Salachas, Francois, additional, Rochat, Julie, additional, Goizet, Cyril, additional, Juntas Morales, Raul, additional, Lumbroso, Serge, additional, Philibert, Pascal, additional, Cheillan, David, additional, and Mouzat, Kevin, additional

Published
2023
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9. Genetic screening of ANXA11 revealed novel mutations linked to amyotrophic lateral sclerosis

Author

Teyssou, Elisa, Muratet, François, Amador, Maria-Del-Mar, Ferrien, Mélanie, Lautrette, Géraldine, Machat, Selma, Boillée, Séverine, Larmonier, Thierry, Saker, Safaa, Leguern, Eric, Cazeneuve, Cécile, Marie, Yannick, Guegan, Justine, Gyorgy, Beata, Cintas, Pascal, Meininger, Vincent, Le Forestier, Nadine, Salachas, François, Couratier, Philippe, Camu, William, Seilhean, Danielle, and Millecamps, Stéphanie

Published
2021
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10. Heterozygous SPTLC1 p.Leu39del is a major cause of slow- progressing juvenile ALS.

Author

Guissart, Claire, De la Cruz, Elisa, Flabeau, Olivier, Grapperon, Aude-Marie, Corazza, Giovanni, Junilhon, Lucie, Delmas, Jean- Charles, Millecamps, Stéphanie, Polge, Anne, Amador, Maria del Mar, Salachas, Francois, Rochat, Julie, Goizet, Cyril, Juntas Morales, Raul, Lumbroso, Serge, Philibert, Pascal, Cheillan, David, and Mouzat, Kevin

Subjects
MOTOR neuron diseases, AMYOTROPHIC lateral sclerosis, LIQUID chromatography-mass spectrometry
Abstract

This article presents a study on juvenile amyotrophic lateral sclerosis (JALS), a rare motor neuron disease that affects individuals under 25 years old. The study focuses on the SPTLC1 gene, which has been linked to JALS. Researchers identified a specific mutation in the SPTLC1 gene, known as p.Leu39del, and found that it is a major cause of JALS. The study also explores the lipid profile of patients with this mutation and suggests that lipid dysmetabolism could be used as biomarkers and therapeutic targets for JALS. The research provides important insights for the genetic diagnosis of JALS and highlights the need for further investigation into SPTLC1 mutations. [Extracted from the article]

Published
2024
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12. Multicenter evaluation of neurofilaments in early symptom onset amyotrophic lateral sclerosis

Author

Feneberg, Emily, Oeckl, Patrick, Steinacker, Petra, Verde, Federico, Barro, Christian, Van Damme, Philip, Gray, Elizabeth, Grosskreutz, Julian, Jardel, Claude, Kuhle, Jens, Koerner, Sonja, Lamari, Foudil, Amador, Maria del Mar, Mayer, Benjamin, Morelli, Claudia, Muckova, Petra, Petri, Susanne, Poesen, Koen, Raaphorst, Joost, Salachas, François, Silani, Vincenzo, Stubendorff, Beatrice, Turner, Martin R., Verbeek, Marcel M., Weishaupt, Jochen H., Weydt, Patrick, Ludolph, Albert C., and Otto, Markus

Published
2018
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13. Clinical trials in pediatric ALS: a TRICALS feasibility study

Author

Kliest, Tessa, Van Eijk, Ruben P.A., Al-Chalabi, Ammar, Albanese, Alberto, Andersen, Peter M., Amador, Maria Del Mar, Bråthen, Geir, Brunaud-Danel, Veronique, Brylev, Lev, Camu, William, De Carvalho, Mamede, Cereda, Cristina, Cetin, Hakan, Chaverri, Delia, Chiò, Adriano, Corcia, Philippe, Couratier, Philippe, De Marchi, Fabiola, Desnuelle, Claude, Van Es, Michael A., Esteban, JesÚs, Filosto, Massimiliano, GarcÍa Redondo, Alberto, Grosskreutz, Julian, Hanemann, Clemens O., Holmøy, Trygve, Høyer, Helle, Ingre, Caroline, Koritnik, Blaz, Kuzma-Kozakiewicz, Magdalena, Lambert, Thomas, Leigh, Peter N., Lunetta, Christian, Mandrioli, Jessica, Mcdermott, Christopher J., Meyer, Thomas, Mora, Jesus S., Petri, Susanne, Povedano, Mónica, Reviers, Evy, Riva, Nilo, Roes, Kit C.B., Rubio, Miguel Á., Salachas, François, Sarafov, Stayko, Sorarù, Gianni, Stevic, Zorica, Svenstrup, Kirsten, Møller, Anette Torvin, Turner, Martin R., Van Damme, Philip, Van Leeuwen, Lucie A.G., Varona, Luis, VÁzquez Costa, Juan F., Weber, Markus, Hardiman, Orla, Van Den Berg, Leonard H., Kliest, Tessa, Van Eijk, Ruben P.A., Al-Chalabi, Ammar, Albanese, Alberto, Andersen, Peter M., Amador, Maria Del Mar, Bråthen, Geir, Brunaud-Danel, Veronique, Brylev, Lev, Camu, William, De Carvalho, Mamede, Cereda, Cristina, Cetin, Hakan, Chaverri, Delia, Chiò, Adriano, Corcia, Philippe, Couratier, Philippe, De Marchi, Fabiola, Desnuelle, Claude, Van Es, Michael A., Esteban, JesÚs, Filosto, Massimiliano, GarcÍa Redondo, Alberto, Grosskreutz, Julian, Hanemann, Clemens O., Holmøy, Trygve, Høyer, Helle, Ingre, Caroline, Koritnik, Blaz, Kuzma-Kozakiewicz, Magdalena, Lambert, Thomas, Leigh, Peter N., Lunetta, Christian, Mandrioli, Jessica, Mcdermott, Christopher J., Meyer, Thomas, Mora, Jesus S., Petri, Susanne, Povedano, Mónica, Reviers, Evy, Riva, Nilo, Roes, Kit C.B., Rubio, Miguel Á., Salachas, François, Sarafov, Stayko, Sorarù, Gianni, Stevic, Zorica, Svenstrup, Kirsten, Møller, Anette Torvin, Turner, Martin R., Van Damme, Philip, Van Leeuwen, Lucie A.G., Varona, Luis, VÁzquez Costa, Juan F., Weber, Markus, Hardiman, Orla, and Van Den Berg, Leonard H.

Abstract

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA). Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe. Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS. Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS. Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.

Published
2022
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14. Clinical trials in pediatric ALS: a TRICALS feasibility study

Author

Kliest, Tessa, primary, Van Eijk, Ruben P.A., additional, Al-Chalabi, Ammar, additional, Albanese, Alberto, additional, Andersen, Peter M., additional, Amador, Maria Del Mar, additional, BrÅthen, Geir, additional, Brunaud-Danel, Veronique, additional, Brylev, Lev, additional, Camu, William, additional, De Carvalho, Mamede, additional, Cereda, Cristina, additional, Cetin, Hakan, additional, Chaverri, Delia, additional, Chiò, Adriano, additional, Corcia, Philippe, additional, Couratier, Philippe, additional, De Marchi, Fabiola, additional, Desnuelle, Claude, additional, Van Es, Michael A., additional, Esteban, JesÚs, additional, Filosto, Massimiliano, additional, GarcÍa Redondo, Alberto, additional, Grosskreutz, Julian, additional, Hanemann, Clemens O., additional, HolmØy, Trygve, additional, HØyer, Helle, additional, Ingre, Caroline, additional, Koritnik, Blaz, additional, Kuzma-Kozakiewicz, Magdalena, additional, Lambert, Thomas, additional, Leigh, Peter N., additional, Lunetta, Christian, additional, Mandrioli, Jessica, additional, Mcdermott, Christopher J., additional, Meyer, Thomas, additional, Mora, Jesus S., additional, Petri, Susanne, additional, Povedano, MÓnica, additional, Reviers, Evy, additional, Riva, Nilo, additional, Roes, Kit C.B., additional, Rubio, Miguel Á., additional, Salachas, FranÇois, additional, Sarafov, Stayko, additional, SorarÙ, Gianni, additional, Stevic, Zorica, additional, Svenstrup, Kirsten, additional, MØller, Anette Torvin, additional, Turner, Martin R., additional, Van Damme, Philip, additional, Van Leeuwen, Lucie A.G., additional, Varona, Luis, additional, VÁzquez Costa, Juan F., additional, Weber, Markus, additional, Hardiman, Orla, additional, and Van Den Berg, Leonard H., additional

Published
2022
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16. Novel UBQLN2 mutations linked to amyotrophic lateral sclerosis and atypical hereditary spastic paraplegia phenotype through defective HSP70-mediated proteolysis

Author

Teyssou, Elisa, Chartier, Laura, Amador, Maria-Del-Mar, Lam, Roselina, Lautrette, Géraldine, Nicol, Marie, Machat, Selma, Da Barroca, Sandra, Moigneu, Carine, Mairey, Mathilde, Larmonier, Thierry, Saker, Safaa, Dussert, Christelle, Forlani, Sylvie, Fontaine, Bertrand, Seilhean, Danielle, Bohl, Delphine, Boillée, Séverine, Meininger, Vincent, Couratier, Philippe, Salachas, François, Stevanin, Giovanni, and Millecamps, Stéphanie

Published
2017
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20. Impact of a frequent nearsplice SOD1 variant in amyotrophic lateral sclerosis: optimising SOD1 genetic screening for gene therapy opportunities

Author

Muratet, François, primary, Teyssou, Elisa, additional, Chiot, Aude, additional, Boillée, Séverine, additional, Lobsiger, Christian S, additional, Bohl, Delphine, additional, Gyorgy, Beata, additional, Guegan, Justine, additional, Marie, Yannick, additional, Amador, Maria del Mar, additional, Salachas, Francois, additional, Meininger, Vincent, additional, Bernard, Emilien, additional, Antoine, Jean-Christophe, additional, Camdessanché, Jean-Philippe, additional, Camu, William, additional, Cazeneuve, Cécile, additional, Fauret-Amsellem, Anne-Laure, additional, Leguern, Eric, additional, Mouzat, Kevin, additional, Guissart, Claire, additional, Lumbroso, Serge, additional, Corcia, Philippe, additional, Vourc'h, Patrick, additional, Grapperon, Aude-Marie, additional, Attarian, Shahram, additional, Verschueren, Annie, additional, Seilhean, Danielle, additional, and Millecamps, Stéphanie, additional

Published
2021
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21. Who and Why? Requests for Presymptomatic Genetic Testing for Amyotrophic Lateral Sclerosis/Frontotemporal Dementia vs Huntington Disease

Author

Amador, Maria del Mar, primary, Gargiulo, Marcela, additional, Boucher, Christilla, additional, Herson, Ariane, additional, Staraci, Stéphanie, additional, Salachas, François, additional, Clot, Fabienne, additional, Cazeneuve, Cécile, additional, Le Ber, Isabelle, additional, and Durr, Alexandra, additional

Published
2020
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22. Homoplasmic deleterious MT-ATP6/8 mutations in adult patients

Author

Rucheton, Benoit, primary, Jardel, Claude, additional, Filaut, Sandrine, additional, Amador, Maria del Mar, additional, Maisonobe, Thierry, additional, Serre, Isabelle, additional, Romero, Norma Beatriz, additional, Leonard-Louis, Sarah, additional, Haraux, Francis, additional, and Lombès, Anne, additional

Published
2020
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25. Impact of a frequent nearsplice variant in amyotrophic lateral sclerosis: optimising genetic screening for gene therapy opportunities.

Author

Muratet, François, Teyssou, Elisa, Chiot, Aude, Boillée, Séverine, Lobsiger, Christian S., Bohl, Delphine, Gyorgy, Beata, Guegan, Justine, Marie, Yannick, Amador, Maria Del Mar, Salachas, Francois, Meininger, Vincent, Bernard, Emilien, Antoine, Jean-Christophe, Camdessanché, Jean-Philippe, Camu, William, Cazeneuve, Cécile, Fauret-Amsellem, Anne-Laure, Leguern, Eric, and Mouzat, Kevin

Subjects
AMYOTROPHIC lateral sclerosis, FRONTOTEMPORAL lobar degeneration, GENETIC testing, GENE therapy, SPINAL muscular atrophy, LYMPHOBLASTOID cell lines, RESEARCH, GENETIC mutation, SEQUENCE analysis, RESEARCH methodology, MEDICAL cooperation, EVALUATION research, COMPARATIVE studies, GENETIC techniques, GENEALOGY, PHENOTYPES
Abstract

Objective: Mutations in superoxide dismutase 1 gene (SOD1), encoding copper/zinc superoxide dismutase protein, are the second most frequent high penetrant genetic cause for amyotrophic lateral sclerosis (ALS) motor neuron disease in populations of European descent. More than 200 missense variants are reported along the SOD1 protein. To limit the production of these aberrant and deleterious SOD1 species, antisense oligonucleotide approaches have recently emerged and showed promising effects in clinical trials. To offer the possibility to any patient with SOD1-ALS to benefit of such a gene therapy, it is necessary to ascertain whether any variant of unknown significance (VUS), detected for example in SOD1 non-coding sequences, is pathogenic.Methods: We analysed SOD1 mutation distribution after SOD1 sequencing in a large cohort of 470 French familial ALS (fALS) index cases.Results: We identified a total of 27 SOD1 variants in 38 families including two SOD1 variants located in nearsplice or intronic regions of the gene. The pathogenicity of the c.358-10T>G nearsplice SOD1 variant was corroborated based on its high frequency (as the second most frequent SOD1 variant) in French fALS, the segregation analysis confirmed in eight affected members of a large pedigree, the typical SOD1-related phenotype observed (with lower limb onset and prominent lower motor neuron involvement), and findings on postmortem tissues showing SOD1 misaccumulation.Conclusions: Our results highlighted nearsplice/intronic mutations in SOD1 are responsible for a significant portion of French fALS and suggested the systematic analysis of the SOD1 mRNA sequence could become the method of choice for SOD1 screening, not to miss these specific cases. [ABSTRACT FROM AUTHOR]

Published
2021
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26. Cursive Eye-Writing With Smooth-Pursuit Eye-Movement Is Possible in Subjects With Amyotrophic Lateral Sclerosis

Author

Lenglet, Timothée, primary, Mirault, Jonathan, additional, Veyrat-Masson, Marie, additional, Funkiewiez, Aurélie, additional, Amador, Maria del Mar, additional, Bruneteau, Gaelle, additional, Le Forestier, Nadine, additional, Pradat, Pierre-Francois, additional, Salachas, Francois, additional, Vacher, Yannick, additional, Lacomblez, Lucette, additional, and Lorenceau, Jean, additional

Published
2019
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28. Four-dimensional digital subtraction angiography for exploration of spinal cord vascular malformations: preliminary experience.

Author

Clarençon, Frédéric, Lenck, Stéphanie, Shotar, Eimad, Boch, Anne-Laure, Lefevre, Etienne, Premat, Kevin, Amador, Maria Del Mar, and Sourour, Nader-Antoine

Subjects
BLOOD-vessel abnormalities, DIGITAL subtraction angiography, SPINAL cord, SPINAL cord diseases, INTER-observer reliability, RETROSPECTIVE studies, ARTERIOVENOUS malformation, GENERAL anesthesia
Abstract

Background The precise understanding of the angioarchitecture of spinal vascular malformations (SVMs) is often difficult to reach with conventional digital subtraction angiography (DSA). The purpose of our study was to evaluate the potential of four-dimensional DSA (4D-DSA) (Siemens Healthcare) in the exploration of SVMs. Methods We retrospectively studied all patients who underwent spinal DSA, including 4D-DSA acquisition, from July 2018 to June 2019 at a single institution. All spinal DSA acquisitions were performed under general anesthesia. 4D-DSA acquisitions were acquired with the protocol '12 s DSA Dyna4D Neuro'. 12 mL of iodixanol 320 mg iodine/mL were injected via a 5 F catheter (1 mL/s during the 12 s 4D-DSA acquisition). Interrater (three independent reviewers) and intermodality agreements were assessed. results Nine consecutive patients (six men, three women, mean age 55.3±19.8 years) with 10 SVMs (spinal dural arteriovenous fistulas n=3, spinal epidural arteriovenous fistulas n=2, spinal pial arteriovenous fistulas n=2, and spinal arteriovenous malformations n=2; one patient had two synchronous pial fistulas) had spinal DSA, including 4D-DSA acquisition. Inter-rater agreement was good and moderate for the venous drainage pattern and the SVM subtype, respectively. In 9 of 10 cases, the quality of the acquisition was graded as good. Satisfactory concordance between 4D-DSA and the selective microcatheterization was observed in 90% of cases for the location of the shunt point. Conclusion 4D-DSA acquisition may be helpful for a better understanding of the angioarchitecture of SVMs. Larger series are warranted to confirm these preliminary results. [ABSTRACT FROM AUTHOR]

Published
2021
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30. Multicenter evaluation of neurofilaments in early symptom onset amyotrophic lateral sclerosis

Author

Feneberg, Emily, primary, Oeckl, Patrick, additional, Steinacker, Petra, additional, Verde, Federico, additional, Barro, Christian, additional, Van Damme, Philip, additional, Gray, Elizabeth, additional, Grosskreutz, Julian, additional, Jardel, Claude, additional, Kuhle, Jens, additional, Koerner, Sonja, additional, Lamari, Foudil, additional, Amador, Maria del Mar, additional, Mayer, Benjamin, additional, Morelli, Claudia, additional, Muckova, Petra, additional, Petri, Susanne, additional, Poesen, Koen, additional, Raaphorst, Joost, additional, Salachas, François, additional, Silani, Vincenzo, additional, Stubendorff, Beatrice, additional, Turner, Martin R., additional, Verbeek, Marcel M., additional, Weishaupt, Jochen H., additional, Weydt, Patrick, additional, Ludolph, Albert C., additional, and Otto, Markus, additional

Published
2017
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31. Multicenter Validation Of Csf Neurofilaments As Diagnostic Biomarkers For Als

Author

Oeckl, Patrick, Jardel, Claude, Salachas, Francois, Lamari, Foudil, Andersen, Peter M., Bowser, Robert, de Carvalho, Mamede, Costa, Julia, van Damme, Philip, Gray, Elizabeth, Grosskreutz, Julian, Hernandez-Barral, Maria, Herukka, Sanna-Kaisa, Huss, Andre, Jeromin, Andreas, Kirby, Janine, Kuzma-Kozakiewicz, Magdalena, Amador, Maria del Mar, Mora, Jesus S., and Morelli, Claudia

Abstract

OBJECTIVE: Neurofilaments are leading neurochemical biomarkers for amyotrophic lateral sclerosis (ALS). Here, we investigated the effect of preanalytical factors on neurofilament concentrations in cerebrospinal fluid (CSF) in a reverse round-robin with 15 centers across Europe/U.S. METHODS: Samples from ALS and control patients (5/5 each center, n=150) were analyzed for phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) at two laboratories. RESULTS: CSF pNfH was increased (p568.5pg/mL for pNfH (sensitivity 78.7%, specificity 93.3%) and >1,431pg/mL for NfL (sensitivity 79.0%, specificity 86.4%). CONCLUSION: Values in ALS patients are already comparable between most centers, supporting eventual implementation into clinical routine. However, continuous quality control programs will be necessary for inclusion in the diagnostic work-up.

Published
2016

32. Impact of a frequent nearsplice SOD1variant in amyotrophic lateral sclerosis: optimising SOD1genetic screening for gene therapy opportunities

Author

Muratet, Francois, Teyssou, Elisa, Chiot, Aude, Boillée, Séverine, Lobsiger, Christian S, Bohl, Delphine, Gyorgy, Beata, Guegan, Justine, Marie, Yannick, Amador, Maria del Mar, Salachas, Francois, Meininger, Vincent, Bernard, Emilien, Antoine, Jean-Christophe, Camdessanché, Jean-Philippe, Camu, William, Cazeneuve, Cécile, Fauret-Amsellem, Anne-Laure, Leguern, Eric, Mouzat, Kevin, Guissart, Claire, Lumbroso, Serge, Corcia, Philippe, Vourc'h, Patrick, Grapperon, Aude-Marie, Attarian, Shahram, Verschueren, Annie, Seilhean, Danielle, and Millecamps, Stéphanie

Abstract

ObjectiveMutations in superoxide dismutase 1 gene (SOD1), encoding copper/zinc superoxide dismutase protein, are the second most frequent high penetrant genetic cause for amyotrophic lateral sclerosis (ALS) motor neuron disease in populations of European descent. More than 200 missense variants are reported along the SOD1 protein. To limit the production of these aberrant and deleterious SOD1 species, antisense oligonucleotide approaches have recently emerged and showed promising effects in clinical trials. To offer the possibility to any patient with SOD1-ALS to benefit of such a gene therapy, it is necessary to ascertain whether any variant of unknown significance (VUS), detected for example in SOD1non-coding sequences, is pathogenic.MethodsWe analysed SOD1 mutation distribution after SOD1 sequencing in a large cohort of 470 French familial ALS (fALS) index cases.ResultsWe identified a total of 27 SOD1 variants in 38 families including two SOD1 variants located in nearsplice or intronic regions of the gene. The pathogenicity of the c.358–10T>G nearsplice SOD1variant was corroborated based on its high frequency (as the second most frequent SOD1 variant) in French fALS, the segregation analysis confirmed in eight affected members of a large pedigree, the typical SOD1-related phenotype observed (with lower limb onset and prominent lower motor neuron involvement), and findings on postmortem tissues showing SOD1 misaccumulation.ConclusionsOur results highlighted nearsplice/intronic mutations in SOD1are responsible for a significant portion of French fALS and suggested the systematic analysis of the SOD1mRNA sequence could become the method of choice for SOD1screening, not to miss these specific cases.

Published
2021
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35. Cerebrospinal fluid metabolomics highlights dysregulation of energy metabolism in overt hepatic encephalopathy

Author

Weiss, Nicolas, primary, Barbier Saint Hilaire, Pierre, additional, Colsch, Benoit, additional, Isnard, Foucauld, additional, Attala, Suleiman, additional, Schaefer, Augustin, additional, Amador, Maria del Mar, additional, Rudler, Marika, additional, Lamari, Foudil, additional, Sedel, Frédéric, additional, Thabut, Dominique, additional, and Junot, Christophe, additional

Published
2016
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38. Multicenter validation of CSF neurofilaments as diagnostic biomarkers for ALS

Author

Oeckl, Patrick, primary, Jardel, Claude, additional, Salachas, François, additional, Lamari, Foudil, additional, Andersen, Peter M., additional, Bowser, Robert, additional, de Carvalho, Mamede, additional, Costa, Júlia, additional, van Damme, Philip, additional, Gray, Elizabeth, additional, Grosskreutz, Julian, additional, Hernández-Barral, María, additional, Herukka, Sanna-Kaisa, additional, Huss, André, additional, Jeromin, Andreas, additional, Kirby, Janine, additional, Kuzma-Kozakiewicz, Magdalena, additional, Amador, Maria del Mar, additional, Mora, Jesús S., additional, Morelli, Claudia, additional, Muckova, Petra, additional, Petri, Susanne, additional, Poesen, Koen, additional, Rhode, Heidrun, additional, Rikardsson, Anna-Karin, additional, Robberecht, Wim, additional, Rodríguez Mahillo, Ana I., additional, Shaw, Pamela, additional, Silani, Vincenzo, additional, Steinacker, Petra, additional, Turner, Martin R., additional, Tüzün, Erdem, additional, Yetimler, Berrak, additional, Ludolph, Albert C., additional, and Otto, Markus, additional

Published
2016
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41. HeterozygousHTRA1mutations are associated with autosomal dominant cerebral small vessel disease

Author

Verdura, Edgard, primary, Hervé, Dominique, additional, Scharrer, Eva, additional, Amador, Maria del Mar, additional, Guyant-Maréchal, Lucie, additional, Philippi, Anne, additional, Corlobé, Astrid, additional, Bergametti, Françoise, additional, Gazal, Steven, additional, Prieto-Morin, Carol, additional, Beaufort, Nathalie, additional, Le Bail, Benoit, additional, Viakhireva, Irina, additional, Dichgans, Martin, additional, Chabriat, Hugues, additional, Haffner, Christof, additional, and Tournier-Lasserve, Elisabeth, additional

Published
2015
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43. Dysregulation of muscle cholesterol transport in amyotrophic lateral sclerosis.

Author

Sapaly D, Cheguillaume F, Weill L, Clerc Z, Biondi O, Bendris S, Buon C, Slika R, Piller E, Sundaram VK, da Silva Ramos A, Amador MDM, Lenglet T, Debs R, Le Forestier N, Pradat PF, Salachas F, Lacomblez L, Hesters A, Borderie D, Devos D, Desnuelle C, Rolland AS, Periou B, Vasseur S, Chapart M, Le Ber I, Fauret-Amsellem AL, Millecamps S, Maisonobe T, Leonard-Louis S, Behin A, Authier FJ, Evangelista T, Charbonnier F, and Bruneteau G

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons, with a typical lifespan of 3-5 years. Altered metabolism is a key feature of ALS that strongly influences prognosis, with an increase in whole-body energy expenditure and changes in skeletal muscle metabolism, including greater reliance on fat oxidation. Dyslipidemia has been described in ALS as part of the metabolic dysregulation, but its role in the pathophysiology of the disease remains controversial. Among the lipids, cholesterol is of particular interest as a vital component of cell membranes, playing a key role in signal transduction and mitochondrial function in muscle. The aim of this study was to investigate whether motor dysfunction in ALS might be associated with dysregulation of muscle cholesterol metabolism. We determined cholesterol content and analyzed the expression of key determinants of the cholesterol metabolism pathway in muscle biopsies from thirteen ALS patients and ten asymptomatic ALS-mutation gene carriers compared to sixteen controls. Using human control primary myotubes, we further investigated the potential contribution of cholesterol dyshomeostasis to reliance on mitochondrial fatty acid. We found that cholesterol accumulates in the skeletal muscle of ALS patients and that cholesterol overload significantly correlates with disease severity evaluated by the Revised ALS Functional Rating Scale. These defects are associated with overexpression of the genes of the lysosomal cholesterol transporters Niemann-Pick type C1 (NPC1) and 2 (NPC2), which are required for cholesterol transfer from late endosomes/lysosomes to cellular membranes. Most notably, a significant increase in NPC2 mRNA levels could be detected in muscle samples from asymptomatic ALS-mutation carriers, long before disease onset. We found that filipin-stained unesterified cholesterol accumulated in the lysosomal compartment in ALS muscle samples, suggesting dysfunction of the NPC1/2 system. Accordingly, we report here that experimental NPC1 inhibition or lysosomal pH alteration in human primary myotubes was sufficient to induce the overexpression of NPC1 and NPC2 mRNA. Finally, acute NPC1 inhibition in human control myotubes induced a shift towards a preferential use of fatty acids, thus reproducing the metabolic defect characteristic of ALS muscle. We conclude that cholesterol homeostasis is dysregulated in ALS muscle from the presymptomatic stage. Targeting NPC1/2 dysfunction may be a new therapeutic strategy for ALS to restore muscle energy metabolism and slow motor symptom progression., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Published
2024
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44. Cognitive impairment in children and adults with cerebrotendinous xanthomatosis: A French cohort study.

Author

Salardaine Q, Shor N, Villain N, Bozon F, Amador MDM, Duchon C, Mélé N, Schiff M, Brassier A, and Nadjar Y

Abstract

Cerebrotendinous xanthomatosis is a rare and treatable metabolic disorder related to the accumulation of cholestanol. This disorder is primarily associated with motor and cognitive impairments, although the latter has not been extensively characterized. The objectives of this work were to define the cognitive profile found in cerebrotendinous xanthomatosis patients, investigate the progression of cognitive impairment over time, and search for radio-clinical correlations. Through a multicentric chart review study, we collected cognitive and radiological data from nine children and eighteen adults with genetically proven cerebrotendinous xanthomatosis. We performed a volumetric and morphological analysis of the brain magnetic resonance imaging. In our cohort, 44% (4/9) of children and 78% (14/18) of adults exhibited cognitive impairment that can be severe. The study revealed a significant impairment in various cognitive domains, specifically executive, attentional, language, and visuo-spatial. Among adults, 16% (3/18) developed dementia after age 50. These three patients had delayed chenodeoxycholic acid treatment and important cerebral atrophy. Besides these three cases of late-onset cognitive decline, Mini-Mental State Evaluation was generally stable, suggesting cognitive impairment due to a neurodevelopmental disorder and persisting in adulthood. Cognitive impairment was less common in children, possibly related to early chenodeoxycholic acid treatment in our cohort. The severity of magnetic resonance imaging abnormalities did not predict cognitive impairment in patients. Overall, in cerebrotendinous xanthomatosis, cognitive impairment can be severe and mainly neurodevelopmental. Early chenodeoxycholic acid treatment might be associated with a reduced risk of cognitive decline., (© 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Published
2024
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45. Involvement of peripheral III nerve in multiple sclerosis patient: Report of a new case and discussion of the underlying mechanism.

Author

Shor N, Amador MD, Dormont D, Lubetzki C, and Bertrand A

Subjects
Adult, Female, Humans, Magnetic Resonance Imaging methods, Multiple Sclerosis, Relapsing-Remitting diagnosis, Peripheral Nervous System Diseases diagnosis, Multiple Sclerosis, Relapsing-Remitting pathology, Myelin Sheath pathology, Peripheral Nervous System Diseases pathology, Trigeminal Nerve pathology
Abstract

Multiple sclerosis (MS) is a chronic disorder that affects the central nervous system myelin. However, a few radiological cases have documented an involvement of peripheral cranial nerves, within the subarachnoid space, in MS patients. We report the case of a 36-year-old female with a history of relapsing-remitting (RR) MS who consulted for a subacute complete paralysis of the right III nerve. Magnetic resonance imaging (MRI) examination showed enhancement and thickening of the cisternal right III nerve, in continuity with a linear, mesencephalic, acute demyelinating lesion. Radiological involvement of the cisternal part of III nerve has been reported only once in MS patients. Radiological involvement of the cisternal part of V nerve occurs more frequently, in almost 3% of MS patients. In both situations, the presence of a central demyelinating lesion, in continuity with the enhancement of the peripheral nerve, suggests that peripheral nerve damage is a secondary process, rather than a primary target of demyelination.

Published
2017
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