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3. Geographic differences in the incidence of Huntington’s disease in Sardinia, Italy

Author

Muroni, A., Murru, M. R., Ulgheri, L., Sechi, M., Ercoli, T., Marrosu, F., Scaglione, C. L., Bentivoglio, A. R., Petracca, M., Soliveri, P., Cocco, E., Cuccu, S., Deriu, M., Zuccato, C., Defazio, G., Bentivoglio A. R. (ORCID:0000-0002-9663-095X), Petracca M., Muroni, A., Murru, M. R., Ulgheri, L., Sechi, M., Ercoli, T., Marrosu, F., Scaglione, C. L., Bentivoglio, A. R., Petracca, M., Soliveri, P., Cocco, E., Cuccu, S., Deriu, M., Zuccato, C., Defazio, G., Bentivoglio A. R. (ORCID:0000-0002-9663-095X), and Petracca M.

Abstract

Background: The frequency of Huntington’s disease (HD) may vary considerably, with higher estimates in non-Asian populations. We have recently examined the prevalence of HD in the southern part of Sardinia, a large Italian Mediterranean island that is considered a genetic isolate. We observed regional microgeographic differences in the prevalence of HD across the study area similar to those recently reported in other studies conducted in European countries. To explore the basis for this variability, we undertook a study of the incidence of HD in Sardinia over a 10-year period, 2009 to 2018. Methods: Our research was conducted in the 5 administrative areas of Sardinia island. Case patients were ascertained through multiple sources in Sardinia and Italy. Results: During the incidence period 53 individuals were diagnosed with clinically manifested HD. The average annual incidence rate 2009–2018 was 2.92 per 106 persons-year (95% CI, 2.2 to 3.9). The highest incidence rate was observed in South Sardinia (6.3; 95% CI, 4.2–9.5). This rate was significantly higher (p<0.01) than the rates from Cagliari, Oristano, and Sassari provinces but did not significantly differ (p = 0.38) from the Nuoro rate. Conclusions: The overall incidence of HD in Sardinia is close to the correspondent estimates in Mediterranean countries. Our findings highlight also the possibility of local microgeographic variations in the epidemiology of HD that might reflect several factors, including a possible founder effect in the rural areas of South Sardinia and Nuoro.

Published
2021

10. Prevalence of Huntington's disease in Southern Sardinia, Italy

Author

Muroni, A., Murru, M. R., Sechi, M., Ercoli, T., Marrosu, F., Bentivoglio, Anna Rita, Petracca, Martina, Maria Scaglione, C. L., Soliveri, P., Cocco, E., Pedron, M., Murgia, M., Deriu, M., Cuccu, S., Ulgheri, L., Zuccato, C., Defazio, G., Bentivoglio A. R. (ORCID:0000-0002-9663-095X), Petracca M., Muroni, A., Murru, M. R., Sechi, M., Ercoli, T., Marrosu, F., Bentivoglio, Anna Rita, Petracca, Martina, Maria Scaglione, C. L., Soliveri, P., Cocco, E., Pedron, M., Murgia, M., Deriu, M., Cuccu, S., Ulgheri, L., Zuccato, C., Defazio, G., Bentivoglio A. R. (ORCID:0000-0002-9663-095X), and Petracca M.

Abstract

Background: The frequency of Huntington's disease (HD) may vary considerably, with higher estimates in non Asian populations. In Italy, two recent studies performed in Ferrara county and Molise provided different prevalence estimates, varying from 4.2 × 105 to 10.8 × 105. Here we present a study performed in the Southern part of Sardinia, a large Italian mediterranean island that is considered a genetic isolate. Methods: The study area included the two neighbouring counties of South Sardinia and Cagliari with 353,830 and 431,955 inhabitants respectively on December 31st, 2017 (prevalence date). Case-patients were ascertained through multiple sources in Sardinia and Italy. Results: We identified 54 individuals with HD, of whom 47 were alive on prevalence date. The resulting prevalence rate was 5.98 × 105 in the overall study area, however with marked variations between South Sardinia and Cagliari (9.6 × 105 vs. 3.0 × 105, p = 0.02). In the two study areas, we found similar CAG repeat length in normal alleles (17.5 ± 2.1 vs. 17.7 ± 2.2, p = 0.5). Conclusions: The overall prevalence of HD in Sardinia is close to the correspondent estimates in Europeans. Our findings also highlighted the possibility of local microgeographic variations in the epidemiology of HD.

Published
2020

18. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., van Rheenen, Wouter, Murphy, Natalie A., van Vugt, Joke J. F. A., Geiger, Joshua T., van der Spek, Rick, Pliner, Hannah A., Shankaracharya, null, Smith, Bradley N., Marangi, Giuseppe, Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Logullo, Francesco O., Simone, Isabella, Logroscino, Giancarlo, Salvi, Fabrizio, Bartolomei, Ilaria, Borghero, Giuseppe, Murru, Maria Rita, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Marrosu, Francesco, Marrosu, Maria Giovanna, Floris, Gianluca, Cannas, Antonino, Capasso, Margherita, Caponnetto, Claudia, Mancardi, Gianluigi, Origone, Paola, Mandich, Paola, Conforti, Francesca L., Cavallaro, Sebastiano, Mora, Gabriele, Marinou, Kalliopi, Sideri, Riccardo, Penco, Silvana, Mosca, Lorena, Lunetta, Christian, Pinter, Giuseppe Lauria, Corbo, Massimo, Riva, Nilo, Carrera, Paola, Volanti, Paolo, Mandrioli, Jessica, Fini, Nicola, Fasano, Antonio, Tremolizzo, Lucio, Arosio, Alessandro, Ferrarese, Carlo, Trojsi, Francesca, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Piccirillo, Giovanni, Femiano, Cinzia, Ticca, Anna, Ortu, Enzo, La Bella, Vincenzo, Spataro, Rossella, Colletti, Tiziana, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Santarelli, Marialuisa, Petrucci, Antonio, Pugliatti, Maura, Pirisi, Angelo, Parish, Leslie D., Occhineri, Patrizia, Giannini, Fabio, Battistini, Stefania, Ricci, Claudia, Benigni, Michele, Cau, Tea B., Loi, Daniela, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Canosa, Antonio, Ilardi, Antonio, Manera, Umberto, Grassano, Maurizio, Tanel, Raffaella, Pisano, Fabrizio, Mazzini, Letizia, Messina, Sonia, D'Alfonso, Sandra, Corrado, Lucia, Ferrucci, Luigi, Harms, Matthew B., Goldstein, David B., Shneider, Neil A., Goutman, Stephen, Simmons, Zachary, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Manousakis, George, Appel, Stanley, Simpson, Ericka, Wang, Leo, Baloh, Robert H., Gibson, Summer, Bedlack, Richard S., Lacomis, David, Sareen, Dhruv, Sherman, Alexander, Bruijn, Lucie, Penny, Michelle, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Allen, Andrew S., Boone, Braden E., Brown, Robert, Carulli, John P., Chesi, Alessandra, Chung, Wendy K., Cirulli, Elizabeth T., Cooper, Gregory M., Couthouis, Julien, Day-Williams, Aaron G., Dion, Patrick A., Gitler, Aaron D., Glass, Jonathan D., Han, Yujun, Harris, Tim, Hayes, Sebastian D., Jones, Angela L., Keebler, Jonathan, Krueger, Brian J., Lasseigne, Brittany N., Levy, Shawn E., Lu, Yi-Fan, Maniatis, Tom, McKenna-Yasek, Diane, Myers, Richard M., Petrovski, Slavé, Pulst, Stefan M., Raphael, Alya R., Ravits, John M., Ren, Zhong, Rouleau, Guy A., Sapp, Peter C., Sims, Katherine B., Staropoli, John F., Waite, Lindsay L., Wang, Quanli, Wimbish, Jack R., Xin, Winnie W., Phatnani, Hemali, Kwan, Justin, Broach, James R., Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steven, Dardiotis, Efthimios, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos A., Dubnau, Joshua, Nath, Avindra, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Kaye, Julia, Wyman, Stacia, LeNail, Alexander, Lima, Leandro, Rothstein, Jeffrey D., Svendsen, Clive N., Van Eyk, Jenny, Maragakis, Nicholas J., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Wyman, Stacia K., Van Eyk, Jennifer E., Benatar, Michael, Taylor, J. Paul, Wu, Gang, Rampersaud, Evadnie, Wuu, Joanne, Rademakers, Rosa, Züchner, Stephan, Schule, Rebecca, McCauley, Jacob, Hussain, Sumaira, Cooley, Anne, Wallace, Marielle, Clayman, Christine, Barohn, Richard, Statland, Jeffrey, Ravits, John, Swenson, Andrea, Jackson, Carlayne, Trivedi, Jaya, Khan, Shaida, Katz, Jonathan, Jenkins, Liberty, Burns, Ted, Gwathmey, Kelly, Caress, James, McMillan, Corey, Elman, Lauren, Pioro, Erik, Heckmann, Jeannine, So, Yuen, Walk, David, Maiser, Samuel, Zhang, Jinghui, Silani, Vincenzo, Gellera, Cinzia, Ratti, Antonia, Taroni, Franco, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Sorarù, Gianni, Cereda, Cristina, De Marchi, Fabiola, Corti, Stefania, Ceroni, Mauro, Siciliano, Gabriele, Filosto, Massimiliano, Inghilleri, Maurizio, Peverelli, Silvia, Colombrita, Claudia, Poletti, Barbara, Maderna, Luca, Del Bo, Roberto, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, Pensato, Viviana, Castellotti, Barbara, Camu, William, Mouzat, Kevin, Lumbroso, Serge, Corcia, Philippe, Meininger, Vincent, Besson, Gérard, Lagrange, Emmeline, Clavelou, Pierre, Guy, Nathalie, Couratier, Philippe, Vourch, Patrick, Danel, Véronique, Bernard, Emilien, Lemasson, Gwendal, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, ten Asbroek, Anneloor L. M. A., Muñoz-Blanco, José Luis, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, MacGowan, Daniel J. L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Strom, Tim M., Meitinger, Thomas, Shatunov, Aleksey, Van Eijk, Kristel R., de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Bas, Moisse, Mattieu, McLaughlin, Russell L., Van Es, Michael A., Weber, Markus, Boylan, Kevin B., Van Blitterswijk, Marka, Morrison, Karen E., Basak, A. Nazli, Mora, Jesús S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Hardiman, Orla, Williams, Kelly L., Fifita, Jennifer A., Nicholson, Garth A., Blair, Ian P., Esteban-Pérez, Jesús, García-Redondo, Alberto, Al-Chalabi, Ammar, Al Kheifat, Ahmad, Andersen, Peter, Chio, Adriano, Cooper-Knock, Jonathan, Dekker, Annelot, Drory, Vivian, Redondo, Alberto Garcia, Gotkine, Marc, Hide, Winston, Iacoangeli, Alfredo, Glass, Jonathan, Kenna, Kevin, Kiernan, Matthew, Landers, John, McLaughlin, Russell, Mill, Jonathan, Neto, Miguel Mitne, Pardina, Jesus Mora, Morrison, Karen, Newhouse, Stephen, Pinto, Susana, Pulit, Sara, Robberecht, Wim, Shaw, Pamela, Shaw, Chris, Sproviero, William, Tazelaar, Gijs, van Damme, Philip, van den Berg, Leonard, van Eijk, Kristel, van Es, Michael, van Vugt, Joke, Veldink, Jan, Zatz, Mayana, Bauer, Denis C., Twine, Natalie A., Rogaeva, Ekaterina, Zinman, Lorne, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Trojanowski, John Q., Brown, Robert H., van den Berg, Leonard H., Veldink, Jan H., Stone, David J., Tienari, Pentti, Chiò, Adriano, Shaw, Christopher E., Traynor, Bryan J., Landers, John E., Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, 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A., Geiger, Joshua T., van der Spek, Rick, Pliner, Hannah A., Shankaracharya, null, Smith, Bradley N., Marangi, Giuseppe, Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Logullo, Francesco O., Simone, Isabella, Logroscino, Giancarlo, Salvi, Fabrizio, Bartolomei, Ilaria, Borghero, Giuseppe, Murru, Maria Rita, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Marrosu, Francesco, Marrosu, Maria Giovanna, Floris, Gianluca, Cannas, Antonino, Capasso, Margherita, Caponnetto, Claudia, Mancardi, Gianluigi, Origone, Paola, Mandich, Paola, Conforti, Francesca L., Cavallaro, Sebastiano, Mora, Gabriele, Marinou, Kalliopi, Sideri, Riccardo, Penco, Silvana, Mosca, Lorena, Lunetta, Christian, Pinter, Giuseppe Lauria, Corbo, Massimo, Riva, Nilo, Carrera, Paola, Volanti, Paolo, Mandrioli, Jessica, Fini, Nicola, Fasano, Antonio, Tremolizzo, Lucio, Arosio, Alessandro, Ferrarese, Carlo, Trojsi, Francesca, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Piccirillo, Giovanni, Femiano, Cinzia, Ticca, Anna, Ortu, Enzo, La Bella, Vincenzo, Spataro, Rossella, Colletti, Tiziana, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Santarelli, Marialuisa, Petrucci, Antonio, Pugliatti, Maura, Pirisi, Angelo, Parish, Leslie D., Occhineri, Patrizia, Giannini, Fabio, Battistini, Stefania, Ricci, Claudia, Benigni, Michele, Cau, Tea B., Loi, Daniela, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Canosa, Antonio, Ilardi, Antonio, Manera, Umberto, Grassano, Maurizio, Tanel, Raffaella, Pisano, Fabrizio, Mazzini, Letizia, Messina, Sonia, D'Alfonso, Sandra, Corrado, Lucia, Ferrucci, Luigi, Harms, Matthew B., Goldstein, David B., Shneider, Neil A., Goutman, Stephen, Simmons, Zachary, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Manousakis, George, Appel, Stanley, Simpson, Ericka, Wang, Leo, Baloh, Robert H., Gibson, Summer, Bedlack, Richard S., Lacomis, David, Sareen, Dhruv, Sherman, Alexander, Bruijn, Lucie, Penny, Michelle, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Allen, Andrew S., Boone, Braden E., Brown, Robert, Carulli, John P., Chesi, Alessandra, Chung, Wendy K., Cirulli, Elizabeth T., Cooper, Gregory M., Couthouis, Julien, Day-Williams, Aaron G., Dion, Patrick A., Gitler, Aaron D., Glass, Jonathan D., Han, Yujun, Harris, Tim, Hayes, Sebastian D., Jones, Angela L., Keebler, Jonathan, Krueger, Brian J., Lasseigne, Brittany N., Levy, Shawn E., Lu, Yi-Fan, Maniatis, Tom, McKenna-Yasek, Diane, Myers, Richard M., Petrovski, Slavé, Pulst, Stefan M., Raphael, Alya R., Ravits, John M., Ren, Zhong, Rouleau, Guy A., Sapp, Peter C., Sims, Katherine B., Staropoli, John F., Waite, Lindsay L., Wang, Quanli, Wimbish, Jack R., Xin, Winnie W., Phatnani, Hemali, Kwan, Justin, Broach, James R., Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steven, Dardiotis, Efthimios, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos A., Dubnau, Joshua, Nath, Avindra, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Kaye, Julia, Wyman, Stacia, LeNail, Alexander, Lima, Leandro, Rothstein, Jeffrey D., Svendsen, Clive N., Van Eyk, Jenny, Maragakis, Nicholas J., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Wyman, Stacia K., Van Eyk, Jennifer E., Benatar, Michael, Taylor, J. 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Abstract

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS.

Published
2018

19. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Nicolas, A., Kenna, K. P., Renton, A. E., Ticozzi, N., Faghri, F., Chia, R., Dominov, J. A., Kenna, B. J., Nalls, M. A., Keagle, P., Rivera, A. M., van Rheenen, W., Murphy, N. A., van Vugt, J. J. F. A., Geiger, J. T., Van der Spek, R. A., Pliner, H. A., Shankaracharya, Smith, B. N., Marangi, Giuseppe, Topp, S. D., Abramzon, Y., Gkazi, A. S., Eicher, J. D., Kenna, A., Logullo, F. O., Simone, I. L., Logroscino, Giandomenico, Salvi, F., Bartolomei, I., Borghero, G., Murru, M. R., Costantino, E., Pani, C., Puddu, R., Caredda, C., Piras, V., Tranquilli, S., Cuccu, S., Corongiu, D., Melis, M., Milia, A., Marrosu, F., Marrosu, M. G., Floris, G., Cannas, A., Capasso, Monica, Caponnetto, C., Mancardi, G., Origone, P., Mandich, P., Conforti, F. L., Cavallaro, S., Mora, G., Marinou, K., Sideri, R., Penco, S., Mosca, Luigi, Lunetta, C., Pinter, G. L., Corbo, M., Riva, N., Carrera, P., Volanti, P., Mandrioli, J., Fini, N., Fasano, Alfonso, Tremolizzo, L., Arosio, A., Ferrarese, C., Trojsi, F., Tedeschi, G., Monsurro, M. R., Piccirillo, G., Femiano, C., Ticca, A., Ortu, E., La Bella, V., Spataro, R., Colletti, T., Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Santarelli, M., Petrucci, A., Pugliatti, M., Pirisi, A., Parish, L. D., Occhineri, P., Giannini, F., Battistini, S., Ricci, C., Benigni, M., Cau, T. B., Loi, D., Calvo, A., Moglia, C., Brunetti, M., Barberis, M., Restagno, G., Casale, F., Marrali, G., Fuda, G., Ossola, I., Cammarosano, S., Canosa, A., Ilardi, A., Manera, U., Grassano, M., Tanel, R., Pisano, F., Mazzini, L., Messina, S., D'Alfonso, Sandra, Corrado, L., Ferrucci, L., Harms, M. B., Goldstein, D. B., Shneider, N. A., Goutman, S. A., Simmons, Z., Miller, T. M., Chandran, S., Pal, S., Manousakis, G., Appel, S. H., Simpson, E., Wang, L., Baloh, R. H., Gibson, S. B., Bedlack, R., Lacomis, D., Sareen, D., Sherman, A., Bruijn, L., Penny, M., Moreno, C. D. A. M., Kamalakaran, S., Allen, A. S., Boone, B. E., Brown, R. H., Carulli, J. P., Chesi, A., Chung, W. K., Cirulli, E. T., Cooper, G. M., Couthouis, J., Day-Williams, A. G., Dion, P. A., Gitler, A. D., Glass, J. D., Han, Y., Harris, T., Hayes, S. D., Jones, A. L., Keebler, J., Krueger, B. J., Lasseigne, B. N., Levy, S. E., Lu, Y. -F., Maniatis, T., McKenna-Yasek, D., Myers, R. M., Petrovski, S., Pulst, S. M., Raphael, A. R., Ravits, J. M., Ren, Z., Rouleau, G. A., Sapp, P. C., Sims, K. B., Staropoli, J. F., Waite, L. L., Wang, Quanquan, Wimbish, J. R., Xin, W. W., Phatnani, H., Kwan, J., Broach, J., Arcila-Londono, X., Lee, E. B., Van Deerlin, V. M., Fraenkel, E., Ostrow, L. W., Baas, F., Zaitlen, N., Berry, J. D., Malaspina, A., Fratta, P., Cox, G. A., Thompson, L. M., Finkbeiner, S., Dardiotis, E., Hornstein, E., Macgowan, D. J. L., Heiman-Patterson, T., Hammell, M. G., Patsopoulos, N. A., Dubnau, J., Nath, A., Musunuri, R. L., Evani, U. S., Abhyankar, A., Zody, M. C., Kaye, J., Wyman, S. K., Lenail, A., Lima, L., Rothstein, J. D., Svendsen, C. N., Van Eyk, J. E., Maragakis, N. J., Kolb, S. J., Cudkowicz, M., Baxi, E., Benatar, M., Taylor, J. P., Wu, G., Rampersaud, E., Wuu, J., Rademakers, R., Zuchner, S., Schule, R., Mccauley, J., Hussain, S., Cooley, A., Wallace, M., Clayman, C., Barohn, R., Statland, J., Swenson, A., Jackson, C., Trivedi, J., Khan, S., Katz, J., Jenkins, L., Burns, T., Gwathmey, K., Caress, J., Mcmillan, C., Elman, L., Pioro, E. P., Heckmann, J., So, Y., Walk, D., Maiser, S., Zhang, J., Silani, V., Gellera, C., Ratti, A., Taroni, F., Lauria, G., Verde, F., Fogh, I., Tiloca, C., Comi, G. P., Soraru, G., Cereda, C., De Marchi, F., Corti, S., Ceroni, M., Siciliano, Giovanni, Filosto, M., Inghilleri, M., Peverelli, S., Colombrita, C., Poletti, B., Maderna, L., Del Bo, R., Gagliardi, S., Querin, G., Bertolin, C., Pensato, V., Castellotti, B., Camu, W., Mouzat, K., Lumbroso, S., Corcia, P., Meininger, V., Besson, G., Lagrange, E., Clavelou, P., Guy, N., Couratier, P., Vourch, P., Danel, V., Bernard, E., Lemasson, G., Laaksovirta, H., Myllykangas, L., Jansson, L., Valori, Vanna Maria, Ealing, J., Hamdalla, H., Rollinson, S., Pickering-Brown, S., Orrell, R. W., Sidle, K. C., Hardy, J., Singleton, A. B., Johnson, J. O., Arepalli, S., Polak, M., Asress, S., Al-Sarraj, S., King, A., Troakes, C., Vance, C., de Belleroche, J., ten Asbroek, A. L. M. A., Munoz-Blanco, J. L., Hernandez, D. G., Ding, J., Gibbs, J. R., Scholz, S. W., Floeter, M. K., Campbell, R. H., Landi, Francesco, Bowser, R., Kirby, J., Pamphlett, R., Gerhard, G., Dunckley, T. L., Brady, C. B., Kowall, N. W., Troncoso, J. C., Le Ber, I., Heiman-Patterson, T. D., Kamel, F., Van Den Bosch, L., Strom, T. M., Meitinger, T., Shatunov, A., Van Eijk, K. R., de Carvalho, M., Kooyman, M., Middelkoop, B., Moisse, M., Mclaughlin, R. L., Van Es, M. A., Weber, M., Boylan, K. B., Van Blitterswijk, M., Morrison, K. E., Basak, A. N., Mora, J. S., Drory, V. E., Shaw, P. J., Turner, M. R., Talbot, K., Hardiman, O., Williams, K. L., Fifita, J. A., Nicholson, G. A., Blair, I. P., Esteban-Perez, J., Garcia-Redondo, A., Al-Chalabi, A., Al Kheifat, A., Andersen, P. M., Chio, A., Cooper-Knock, J., Dekker, A., Redondo, A. G., Gotkine, M., Hide, W., Iacoangeli, A., Kiernan, M., Landers, J. E., Mill, J., Neto, M. M., Pardina, J. M., Newhouse, S., Pinto, S., Pulit, S., Robberecht, W., Shaw, C., Sproviero, W., Tazelaar, G., Van Damme, P., van den Berg, L. H., van Vugt, J., Veldink, J. H., Zatz, M., Bauer, D. C., Twine, N. A., Rogaeva, E., Zinman, L., Brice, A., Feldman, E. L., Ludolph, A. C., Weishaupt, J. H., Trojanowski, J. Q., Stone, D. J., Tienari, P., Shaw, C. E., Traynor, B. J., Marangi G. (ORCID:0000-0002-6898-8882), Logroscino G. (ORCID:0000-0003-1301-5343), Capasso M., Mosca L. (ORCID:0000-0003-4641-0841), Fasano A., Sabatelli M. (ORCID:0000-0001-6635-4985), Zollino M. (ORCID:0000-0003-4871-9519), Conte A., Luigetti M. (ORCID:0000-0001-7539-505X), Lattante S. (ORCID:0000-0003-2891-0340), D'Alfonso S., Siciliano G., Valori M., Landi F. (ORCID:0000-0002-3472-1389), Nicolas, A., Kenna, K. P., Renton, A. E., Ticozzi, N., Faghri, F., Chia, R., Dominov, J. A., Kenna, B. J., Nalls, M. A., Keagle, P., Rivera, A. M., van Rheenen, W., Murphy, N. A., van Vugt, J. J. F. A., Geiger, J. T., Van der Spek, R. A., Pliner, H. A., Shankaracharya, Smith, B. N., Marangi, Giuseppe, Topp, S. D., Abramzon, Y., Gkazi, A. S., Eicher, J. D., Kenna, A., Logullo, F. O., Simone, I. L., Logroscino, Giandomenico, Salvi, F., Bartolomei, I., Borghero, G., Murru, M. R., Costantino, E., Pani, C., Puddu, R., Caredda, C., Piras, V., Tranquilli, S., Cuccu, S., Corongiu, D., Melis, M., Milia, A., Marrosu, F., Marrosu, M. G., Floris, G., Cannas, A., Capasso, Monica, Caponnetto, C., Mancardi, G., Origone, P., Mandich, P., Conforti, F. L., Cavallaro, S., Mora, G., Marinou, K., Sideri, R., Penco, S., Mosca, Luigi, Lunetta, C., Pinter, G. L., Corbo, M., Riva, N., Carrera, P., Volanti, P., Mandrioli, J., Fini, N., Fasano, Alfonso, Tremolizzo, L., Arosio, A., Ferrarese, C., Trojsi, F., Tedeschi, G., Monsurro, M. R., Piccirillo, G., Femiano, C., Ticca, A., Ortu, E., La Bella, V., Spataro, R., Colletti, T., Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Santarelli, M., Petrucci, A., Pugliatti, M., Pirisi, A., Parish, L. D., Occhineri, P., Giannini, F., Battistini, S., Ricci, C., Benigni, M., Cau, T. B., Loi, D., Calvo, A., Moglia, C., Brunetti, M., Barberis, M., Restagno, G., Casale, F., Marrali, G., Fuda, G., Ossola, I., Cammarosano, S., Canosa, A., Ilardi, A., Manera, U., Grassano, M., Tanel, R., Pisano, F., Mazzini, L., Messina, S., D'Alfonso, Sandra, Corrado, L., Ferrucci, L., Harms, M. B., Goldstein, D. B., Shneider, N. A., Goutman, S. A., Simmons, Z., Miller, T. M., Chandran, S., Pal, S., Manousakis, G., Appel, S. H., Simpson, E., Wang, L., Baloh, R. H., Gibson, S. B., Bedlack, R., Lacomis, D., Sareen, D., Sherman, A., Bruijn, L., Penny, M., Moreno, C. D. A. M., Kamalakaran, S., Allen, A. S., Boone, B. E., Brown, R. H., Carulli, J. P., Chesi, A., Chung, W. K., Cirulli, E. T., Cooper, G. M., Couthouis, J., Day-Williams, A. G., Dion, P. A., Gitler, A. D., Glass, J. D., Han, Y., Harris, T., Hayes, S. D., Jones, A. L., Keebler, J., Krueger, B. J., Lasseigne, B. N., Levy, S. E., Lu, Y. -F., Maniatis, T., McKenna-Yasek, D., Myers, R. M., Petrovski, S., Pulst, S. M., Raphael, A. R., Ravits, J. M., Ren, Z., Rouleau, G. A., Sapp, P. C., Sims, K. B., Staropoli, J. F., Waite, L. L., Wang, Quanquan, Wimbish, J. R., Xin, W. W., Phatnani, H., Kwan, J., Broach, J., Arcila-Londono, X., Lee, E. B., Van Deerlin, V. M., Fraenkel, E., Ostrow, L. W., Baas, F., Zaitlen, N., Berry, J. D., Malaspina, A., Fratta, P., Cox, G. A., Thompson, L. M., Finkbeiner, S., Dardiotis, E., Hornstein, E., Macgowan, D. J. L., Heiman-Patterson, T., Hammell, M. G., Patsopoulos, N. A., Dubnau, J., Nath, A., Musunuri, R. L., Evani, U. S., Abhyankar, A., Zody, M. C., Kaye, J., Wyman, S. K., Lenail, A., Lima, L., Rothstein, J. D., Svendsen, C. N., Van Eyk, J. E., Maragakis, N. J., Kolb, S. J., Cudkowicz, M., Baxi, E., Benatar, M., Taylor, J. P., Wu, G., Rampersaud, E., Wuu, J., Rademakers, R., Zuchner, S., Schule, R., Mccauley, J., Hussain, S., Cooley, A., Wallace, M., Clayman, C., Barohn, R., Statland, J., Swenson, A., Jackson, C., Trivedi, J., Khan, S., Katz, J., Jenkins, L., Burns, T., Gwathmey, K., Caress, J., Mcmillan, C., Elman, L., Pioro, E. P., Heckmann, J., So, Y., Walk, D., Maiser, S., Zhang, J., Silani, V., Gellera, C., Ratti, A., Taroni, F., Lauria, G., Verde, F., Fogh, I., Tiloca, C., Comi, G. P., Soraru, G., Cereda, C., De Marchi, F., Corti, S., Ceroni, M., Siciliano, Giovanni, Filosto, M., Inghilleri, M., Peverelli, S., Colombrita, C., Poletti, B., Maderna, L., Del Bo, R., Gagliardi, S., Querin, G., Bertolin, C., Pensato, V., Castellotti, B., Camu, W., Mouzat, K., Lumbroso, S., Corcia, P., Meininger, V., Besson, G., Lagrange, E., Clavelou, P., Guy, N., Couratier, P., Vourch, P., Danel, V., Bernard, E., Lemasson, G., Laaksovirta, H., Myllykangas, L., Jansson, L., Valori, Vanna Maria, Ealing, J., Hamdalla, H., Rollinson, S., Pickering-Brown, S., Orrell, R. W., Sidle, K. C., Hardy, J., Singleton, A. B., Johnson, J. O., Arepalli, S., Polak, M., Asress, S., Al-Sarraj, S., King, A., Troakes, C., Vance, C., de Belleroche, J., ten Asbroek, A. L. M. A., Munoz-Blanco, J. L., Hernandez, D. G., Ding, J., Gibbs, J. R., Scholz, S. W., Floeter, M. K., Campbell, R. H., Landi, Francesco, Bowser, R., Kirby, J., Pamphlett, R., Gerhard, G., Dunckley, T. L., Brady, C. B., Kowall, N. W., Troncoso, J. C., Le Ber, I., Heiman-Patterson, T. D., Kamel, F., Van Den Bosch, L., Strom, T. M., Meitinger, T., Shatunov, A., Van Eijk, K. R., de Carvalho, M., Kooyman, M., Middelkoop, B., Moisse, M., Mclaughlin, R. L., Van Es, M. A., Weber, M., Boylan, K. B., Van Blitterswijk, M., Morrison, K. E., Basak, A. N., Mora, J. S., Drory, V. E., Shaw, P. J., Turner, M. R., Talbot, K., Hardiman, O., Williams, K. L., Fifita, J. A., Nicholson, G. A., Blair, I. P., Esteban-Perez, J., Garcia-Redondo, A., Al-Chalabi, A., Al Kheifat, A., Andersen, P. M., Chio, A., Cooper-Knock, J., Dekker, A., Redondo, A. G., Gotkine, M., Hide, W., Iacoangeli, A., Kiernan, M., Landers, J. E., Mill, J., Neto, M. M., Pardina, J. M., Newhouse, S., Pinto, S., Pulit, S., Robberecht, W., Shaw, C., Sproviero, W., Tazelaar, G., Van Damme, P., van den Berg, L. H., van Vugt, J., Veldink, J. H., Zatz, M., Bauer, D. C., Twine, N. A., Rogaeva, E., Zinman, L., Brice, A., Feldman, E. L., Ludolph, A. C., Weishaupt, J. H., Trojanowski, J. Q., Stone, D. J., Tienari, P., Shaw, C. E., Traynor, B. J., Marangi G. (ORCID:0000-0002-6898-8882), Logroscino G. (ORCID:0000-0003-1301-5343), Capasso M., Mosca L. (ORCID:0000-0003-4641-0841), Fasano A., Sabatelli M. (ORCID:0000-0001-6635-4985), Zollino M. (ORCID:0000-0003-4871-9519), Conte A., Luigetti M. (ORCID:0000-0001-7539-505X), Lattante S. (ORCID:0000-0003-2891-0340), D'Alfonso S., Siciliano G., Valori M., and Landi F. (ORCID:0000-0002-3472-1389)

Abstract

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS.

Published
2018

20. HFE p.H63D polymorphism does not influence ALS phenotype and survival

Author

Chio, A, Mora, G, Sabatelli, M, Caponnetto, C, Lunetta, C, Traynor, B, Johnson, J, Nalls, M, Calvo, A, Moglia, C, Borghero, G, Monsurro, M, La Bella, V, Volanti, P, Simone, I, Salvi, F, Logullo, F, Nilo, R, Giannini, F, Mandrioli, J, Tanel, R, Murru, M, Mandich, P, Zollino, M, Conforti, F, Penco, S, Brunetti, M, Barberis, M, Restagno, G, Logroscino, G, Bartolomei, I, Capasso, M, Mancardi, G, Origone, P, Marinou, K, Sideri, R, Mosca, L, Pinter, G, Corbo, M, Fini, N, Georgoulopoulou, E, Tremolizzo, L, Tedeschi, G, Trojsi, F, Piccirillo, G, Cristillo, V, Spataro, R, Colletti, T, Conte, A, Luigetti, M, Lattante, S, Marangi, G, Santarelli, M, Petrucci, A, Battistini, S, Ricci, C, Benigni, M, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Ilardi, A, Bertuzzo, D, Pisano, F, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Ticca, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Ortu, E, Cau, T, Loi, D, Chio A., Mora G., Sabatelli M., Caponnetto C., Lunetta C., Traynor B. J., Johnson J. O., Nalls M. A., Calvo A., Moglia C., Borghero G., Monsurro M. R., La Bella V., Volanti P., Simone I., Salvi F., Logullo F. O., Nilo R., Giannini F., Mandrioli J., Tanel R., Murru M. R., Mandich P., Zollino M., Conforti F. L., Penco S., Brunetti M., Barberis M., Restagno G., Logroscino G., Bartolomei I., Capasso M., Mancardi G., Origone P., Marinou K., Sideri R., Mosca L., Pinter G. L., Corbo M., Fini N., Georgoulopoulou E., Tremolizzo L., Tedeschi G., Trojsi F., Piccirillo G., Cristillo V., Spataro R., Colletti T., Conte A., Luigetti M., Lattante S., Marangi G., Santarelli M., Petrucci A., Battistini S., Ricci C., Benigni M., Casale F., Marrali G., Fuda G., Ossola I., Cammarosano S., Ilardi A., Bertuzzo D., Pisano F., Costantino E., Pani C., Puddu R., Caredda C., Piras V., Tranquilli S., Cuccu S., Corongiu D., Melis M., Milia A., Marrosu F., Marrosu M. G., Floris G., Cannas A., Ticca A., Pugliatti M., Pirisi A., Parish L. D., Occhineri P., Ortu E., Cau T. B., Loi D., Chio, A, Mora, G, Sabatelli, M, Caponnetto, C, Lunetta, C, Traynor, B, Johnson, J, Nalls, M, Calvo, A, Moglia, C, Borghero, G, Monsurro, M, La Bella, V, Volanti, P, Simone, I, Salvi, F, Logullo, F, Nilo, R, Giannini, F, Mandrioli, J, Tanel, R, Murru, M, Mandich, P, Zollino, M, Conforti, F, Penco, S, Brunetti, M, Barberis, M, Restagno, G, Logroscino, G, Bartolomei, I, Capasso, M, Mancardi, G, Origone, P, Marinou, K, Sideri, R, Mosca, L, Pinter, G, Corbo, M, Fini, N, Georgoulopoulou, E, Tremolizzo, L, Tedeschi, G, Trojsi, F, Piccirillo, G, Cristillo, V, Spataro, R, Colletti, T, Conte, A, Luigetti, M, Lattante, S, Marangi, G, Santarelli, M, Petrucci, A, Battistini, S, Ricci, C, Benigni, M, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Ilardi, A, Bertuzzo, D, Pisano, F, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Ticca, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Ortu, E, Cau, T, Loi, D, Chio A., Mora G., Sabatelli M., Caponnetto C., Lunetta C., Traynor B. J., Johnson J. O., Nalls M. A., Calvo A., Moglia C., Borghero G., Monsurro M. R., La Bella V., Volanti P., Simone I., Salvi F., Logullo F. O., Nilo R., Giannini F., Mandrioli J., Tanel R., Murru M. R., Mandich P., Zollino M., Conforti F. L., Penco S., Brunetti M., Barberis M., Restagno G., Logroscino G., Bartolomei I., Capasso M., Mancardi G., Origone P., Marinou K., Sideri R., Mosca L., Pinter G. L., Corbo M., Fini N., Georgoulopoulou E., Tremolizzo L., Tedeschi G., Trojsi F., Piccirillo G., Cristillo V., Spataro R., Colletti T., Conte A., Luigetti M., Lattante S., Marangi G., Santarelli M., Petrucci A., Battistini S., Ricci C., Benigni M., Casale F., Marrali G., Fuda G., Ossola I., Cammarosano S., Ilardi A., Bertuzzo D., Pisano F., Costantino E., Pani C., Puddu R., Caredda C., Piras V., Tranquilli S., Cuccu S., Corongiu D., Melis M., Milia A., Marrosu F., Marrosu M. G., Floris G., Cannas A., Ticca A., Pugliatti M., Pirisi A., Parish L. D., Occhineri P., Ortu E., Cau T. B., and Loi D.

Abstract

It has been recently reported that the p.His63Asp polymorphism of the HFE gene accelerates disease progression both in the SOD1 transgenic mouse and in amyotrophic lateral sclerosis (ALS) patients. We have evaluated the effect of HFE p.His63Asp polymorphism on the phenotype in 1351 Italian ALS patients (232 of Sardinian ancestry). Patients were genotyped for the HFE p.His63Asp polymorphism (CC, GC, and GG). All patients were also assessed for C9ORF72, TARDBP, SOD1, and FUS mutations. Of the 1351 ALS patients, 363 (29.2%) were heterozygous (GC) for the p.His63Asp polymorphism and 30 (2.2%) were homozygous for the minor allele (GG). Patients with CC, GC, and GG polymorphisms did not significantly differ by age at onset, site of onset of symptoms, and survival; however, in SOD1 patients with CG or GG polymorphism had a significantly longer survival than those with a CC polymorphism. Differently from what observed in the mouse model of ALS, the HFE p.His63Asp polymorphism has no effect on ALS phenotype in this large series of Italian ALS patients.

Published
2015

21. Genetic counselling in ALS: facts, uncertainties and clinical suggestions

Author

Chio, A., Battistini, Stefania, Calvo, A., Caponnetto, C., Conforti, F. L., Corbo, M., Giannini, Fabio, Mandrioli, J., Mora, G., Sabatelli, M., Ajmone, C., Mastro, E., Pain, D., Mandich, P., Penco, S., Restagno, G., Zollino, M., Surbone, A., Monsurro, M. R., Tedeschi, G., Conte, A., Luigetti, M., Lattante, S., Marangi, G., Volanti, P., Marinou, K., Papetti, L., Lunetta, C., Pintor, G. L., Salvi, F., Bartolomei, I., Quattrone, A., Gambardella, A., Logroscino, G., Simone, I., Pisano, F., Spataro, R., La Bella, V., Colletti, T., Mancardi, G., Origone, P., Sola, P., Borghero, G., Marrosu, F., Marrosu, M. G., Murru, M. R., Floris, G., Cannas, A., Piras, V., Costantino, E., Pani, C., Sotgiu, M. A., Pugliatti, M., Parish, L. D., Cossu, P., Ticca, A., Rodolico, C., Portaro, S., Ricci, Claudia, Moglia, C., Ossola, I., Brunetti, M., Barberis, M., Canosa, A., Cammarosano, S., Bertuzzo, D., Fuda, G., Ilardi, A., Manera, U., Pastore, I., Sproviero, W., Logullo, F., Tanel, R., Chiò, A, Battistini, S, Calvo, A, Caponnetto, C, Conforti, FL, Corbo, M, Giannini, F, Mandrioli, J, Mora, G, Sabatelli, M, Cammarosano, S, Canosa, A, Moglia, C, Ajmone, C, Mastro, E, Pain, D, Mandich, P, Penco, S, Restagno, G, Zollino, M, Surbone, A, Conforti, Fl, Italsgen, Consortium, Among, Collaborator, Tedeschi, Gioacchino, and Surbone, A.

Subjects
medicine.medical_specialty, Genotype, GENETICS, Genetic counseling, Genetic Counseling, Gene mutation, Settore MED/03 - GENETICA MEDICA, medicine, Humans, Genetic Testing, Amyotrophic lateral sclerosis, Genetic discrimination, Psychiatry, Genetic testing, medicine.diagnostic_test, business.industry, Amyotrophic Lateral Sclerosis, medicine.disease, Penetrance, ALS, 3. Good health, Psychiatry and Mental health, Phenotype, Frontotemporal Dementia, Mutation, Surgery, Settore MED/26 - Neurologia, Neurology (clinical), business, Motor neurone disease, Frontotemporal dementia
Abstract

The clinical approach to patients with amyotrophic lateral sclerosis (ALS) has been largely modified by the identification of novel genes, the detection of gene mutations in apparently sporadic patients, and the discovery of the strict genetic and clinical relation between ALS and frontotemporal dementia (FTD). As a consequence, clinicians are increasingly facing the dilemma on how to handle genetic counselling and testing both for ALS patients and their relatives. On the basis of existing literature on genetics of ALS and of other late-onset life-threatening disorders, we propose clinical suggestions to enable neurologists to provide optimal clinical and genetic counselling to patients and families. Genetic testing should be offered to ALS patients who have a first-degree or second-degree relative with ALS, FTD or both, and should be discussed with, but not offered to, all other ALS patients, with special emphasis on its major uncertainties. Presently, genetic testing should not be proposed to asymptomatic at-risk subjects, unless they request it or are enrolled in research programmes. Genetic counselling in ALS should take into account the uncertainties about the pathogenicity and penetrance of some genetic mutations; the possible presence of mutations of different genes in the same individual; the poor genotypic/phenotypic correlation in most ALS genes; and the phenotypic pleiotropy of some genes. Though psychological, social and ethical implications of genetic testing are still relatively unexplored in ALS, we recommend multidisciplinary counselling that addresses all relevant issues, including disclosure of tests results to family members and the risk for genetic discrimination.

Published
2014
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22. ATNX2 is not a regulatory gene in Italian amyotrophic lateral sclerosis patients with C9ORF72 GGGGCC expansion

Author

Chiò, A, Mora, G, Sabatelli, M, Caponnetto, C, Lunetta, C, Traynor, B. J, Johnson, J. O, Nalls, M. A, Calvo, A, Moglia, C, Borghero, G, Trojsi, F, La Bella, V, Volanti, P, Simone, I, Salvi, F, Logullo, F. O, Riva, N, Carrera, P, Giannini, F, Mandrioli, J, Tanel, R, Capasso, M, Tremolizzo, L, Battistini, S, Murru, M. R, Origone, P, Zollino, M, Penco, S, Mazzini, L, D'Alfonso, S, Restagno, G, Brunetti, M, Barberis, M, Conforti, F. L, Logroscino, G, Bartolomei, I, Mancardi, G, Mandich, P, Marinou, K, Sideri, R, Mosca, L, Lauria Pinter, G, Corbo, M, Fini, N, Fasano, A, Arosio, A, Ferrarese, C, Tedeschi, G, Monsurrò, M. R, Piccirillo, G, Femiano, C, Bersano, A, Corrado, L, Bagarotti, A, Spataro, R, Colletti, T, Conte, A, Luigetti, M, Lattante, S, Marangi, G, Santarelli, M, Petrucci, A, Ricci, C, Benigni, M, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Ilardi, A, Manera, U, Bertuzzo, D, Pisano, F, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M. G, Floris, G, Cannas, A, Ticca, A, Pugliatti, M, Pirisi, A, Parish, L. D, Occhineri, P, Ortu, E, Cau, T. B, Loi, D, Chiò, A., Mora, G., Sabatelli, M., Caponnetto, C., Lunetta, C., Traynor, B., Johnson, J., Nalls, M., Calvo, A., Moglia, C., Borghero, G., Trojsi, F., LA BELLA, V., Volanti, P., Simone, I., Salvi, F., Logullo, F., Riva, N., Carrera, P., Giannini, F., Mandrioli, J., Tanel, R., Capasso, M., Tremolizzo, L., Battistini, S., Murru, M., Origone, P., Zollino, M., Penco, S., Mazzini, L., D'Alfonso, S., Restagno, G., Brunetti, M., Barberis, M., Conforti, F., Chiò, Adriano, Mora, Gabriele, Sabatelli, Mario, Caponnetto, Claudia, Lunetta, Christian, Traynor, Bryan J, Johnson, Janel O, Nalls, Mike A, Calvo, Andrea, Moglia, Cristina, Borghero, Giuseppe, Trojsi, Francesca, La Bella, Vincenzo, Volanti, Paolo, Simone, Isabella, Salvi, Fabrizio, Logullo, Francesco O, Riva, Nilo, Carrera, Paola, Giannini, Fabio, Mandrioli, Jessica, Tanel, Raffaella, Capasso, Margherita, Tremolizzo, Lucio, Battistini, Stefania, Murru, Maria Rita, Origone, Paola, Zollino, Marcella, Penco, Silvana, Logroscino, G, Bartolomei, I, Mancardi, G, Mandich, P, Marinou, K, Sideri, R, Mosca, L, Pinter, Gl, Corbo, M, Fini, N, Fasano, A, Arosio, A, Ferrarese, C, Tedeschi, Gioacchino, Monsurro', Maria Rosaria, Piccirillo, G, Femiano, C, Bersano, A, Corrado, L, Bagarotti, A, Spataro, R, Colletti, T, Conte, A, Luigetti, M, Lattante, S, Marangi, G, Santarelli, M, Petrucci, A, Ricci, C, Benigni, M, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Ilardi, A, Manera, U, Bertuzzo, D, Tanel, R, Pisano, F, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, Mg, Floris, G, Cannas, A, Ticca, A, Pugliatti, M, Pirisi, A, Parish, Ld, Occhineri, P, Ortu, E, Cau, Tb, Loi, D, Mazzini, Letizia, D'Alfonso, Sandra, Restagno, Gabriella, Brunetti, Maura, Barberis, Marco, Conforti, Francesca L., Chiò, A, Mora, G, Sabatelli, M, Caponnetto, C, Lunetta, C, Traynor, B, Johnson, J, Nalls, M, Calvo, A, Moglia, C, Borghero, G, Trojsi, F, La Bella, V, Volanti, P, Simone, I, Salvi, F, Logullo, F, Riva, N, Carrera, P, Giannini, F, Mandrioli, J, Capasso, M, Tremolizzo, L, Battistini, S, Murru, M, Origone, P, Zollino, M, Penco, S, Mazzini, L, D'Alfonso, S, Restagno, G, Brunetti, M, Barberis, M, Conforti, F, Lauria Pinter, G, Tedeschi, G, Monsurrò, M, Marrosu, M, Parish, L, and Cau, T

Subjects
Male, 0301 basic medicine, Aging, C9ORF72, Genetic Association Studie, 030105 genetics & heredity, Biology, Settore MED/03 - GENETICA MEDICA, 03 medical and health sciences, 0302 clinical medicine, C9orf72, medicine, Allele, Amyotrophic lateral sclerosis, Amyotrophic lateral sclerosi, Aged, Ataxin-2, Regulator gene, ATXN2, Phenotype, Neuroscience (all), Medicine (all), Developmental Biology, Geriatrics and Gerontology, Neurology (clinical), Genetics, DNA Repeat Expansion, Protein, General Neuroscience, Middle Aged, medicine.disease, 3. Good health, C9orf72 Protein, Italy, Population study, Female, Settore MED/26 - Neurologia, Trinucleotide repeat expansion, 030217 neurology & neurosurgery, Human
Abstract

There are indications that both familial amyotrophic lateral sclerosis (ALS) and sporadic ALS phenotype and prognosis are partly regulated by genetic and environmental factors, supporting the theory that ALS is a multifactorial disease. The aim of this article was to assess the role of ATXN2 intermediate length repeats in a large series of Italian and Sardinian ALS patients and controls carrying a pathogenetic C9ORF72 GGGGCC hexanucleotide repeat. A total of 1972 ALS cases were identified through the database of the Italian ALS Genetic consortium, a collaborative effort including 18 ALS centers throughout Italy. The study population included: (1) 276 Italian and 57 Sardinian ALS cases who carried the C9ORF72 expansion; (2) 1340 Italian and 299 Sardinian ALS cases not carrying the C9ORF72 expansion. A total of healthy 1043 controls were also assessed. Most Italian and Sardinian cases and controls were homozygous for 22/22 or 23/23 repeats or heterozygous for 22/23 repeats of the ATXN2 gene. ATXN2 intermediate length repeats alleles (≥28) were detected in 3 (0.6%) Italian ALS cases carrying the C9ORF72 expansion, in none of the Sardinian ALS cases carrying the expansion, in 60 (4.3%) Italian cases not carrying the expansion, and in 6 (2.0%) Sardinian ALS cases without C9ORF72 expansion. Intermediate length repeat alleles were found in 12 (1.5%) Italian controls and 1 (0.84%) Sardinian controls. Therefore, ALS patients with C9ORF72 expansion showed a lower frequency of ATXN2 polyQ intermediate length repeats than both controls (Italian cases, p = 0.137; Sardinian cases, p = 0.0001) and ALS patients without C9ORF72 expansion (Italian cases, p = 0.005; Sardinian cases, p = 0.178). In our large study on Italian and Sardinian ALS patients with C9ORF72 GGGGCC hexanucleotide repeat expansion, compared to age-, gender- and ethnic-matched controls, ATXN2 polyQ intermediate length does not represent a modifier of ALS risk, differently from non- C9ORF72 mutated patients.

Published
2015

26. Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72

Author

Chiò, A1, Borghero, G, Restagno, G, Mora, G, Drepper, C, Traynor, Bj, Sendtner, M, Brunetti, M, Ossola, I, Calvo, A, Pugliatti, M, Sotgiu, Ma, Murru, Mr, Marrosu, Mg, Marrosu, F, Marinou, K, Mandrioli, J, Sola, P, Caponnetto, C, Mancardi, G, Mandich, P, La Bella, V, Spataro, R, Conte, A, Monsurrò, Mr, Tedeschi, G, Pisano, F, Bartolomei, I, Salvi, F, Lauria Pinter, G, Simone, I, Logroscino, G, Gambardella, A, Quattrone, A, Lunetta, C, Volanti, P, Zollino, M, Penco, S, Battistini, S, Renton, Ae, Majounie, E, Abramzon, Y, Conforti, Fl, Giannini, F, Corbo, M, Sabatelli, M, Moglia, C, Cammarosano, S, Fuda, G, Canosa, A, Gallo, S, Papetti, L, Luigetti, M, Lattante, S, Marangi, G, Colletti, T, Ricci, C, Origone, P, Floris, G, Cannas, A, Piras, V, Parish, Ld, Solinas, G, Ulgheri, L, Ticca, A, Izzo, F, Laiola, A, Trojsi, F., Chiò, A, Borghero, G, Restagno, G, Mora, G, Drepper, C, Traynor, Bj, Sendtner, M, Brunetti, M, Ossola, I, Calvo, A, Pugliatti, M, Sotgiu, Ma, Murru, Mr, Marrosu, Mg, Marrosu, F, Marinou, K, Mandrioli, J, Sola, P, Caponnetto, C, Mancardi, G, Mandich, P, La Bella, V, Spataro, R, Conte, A, Monsurro', Maria Rosaria, Tedeschi, Gioacchino, Pisano, F, Bartolomei, I, Salvi, F, Lauria Pinter, G, Simone, I, Logroscino, G, Gambardella, A, Quattrone, A, Lunetta, C, Volanti, P, Zollino, M, Penco, S, Battistini, S, the ITALSGEN consortium: Moglia, Cristina, Cammarosano, Stefania, Fuda, Giuseppe, Canosa, Antonio, Gallo, Sara, Papetti, Laura, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Colletti, Tiziana, Ricci, Claudia, Origone, Paola, Floris, Gianluca, Cannas, Antonino, Piras, Valeria, Parish, Leslie D, Solinas, Giuliana, Ulgheri, Lucia, Ticca, Anna, Izzo, Francesco, Laiola, Anna, Trojsi, Francesca, Renton, Ae, Majounie, E, Abramzon, Y, Conforti, Fl, Giannini, F, Corbo, M, Sabatelli, M., Chiò, A., Borghero, G., Restagno, G., Mora, G., Drepper, C., Traynor, B., Sendtner, M., Brunetti, M., Ossola, I., Calvo, A., Pugliatti, M., Sotgiu, M., Murru, M., Marrosu, G., Marrosu, F., Marinou, K., Mandrioli, J., Sola, P., Caponnetto, C., Mancardi, G., Mandich, P., LA BELLA, V., Spataro, R., Conte, A., Monsurrò, M., Tedeschi, G., Pisano, F., Bartolomei, I., Salvi, F., Lauria, G., Simone, I., Logroscino, G., Gambardella, A., Quattrone, A., Lunetta, C., Volanti, P., Zollino, M., Penco, S., Battistini, S., the ITALSGEN, C., Renton, A., Majounie, E., Abramzon, Y., Conforti, F., Giannini, F., and Corbo, M.

Subjects
Male, Parents, Pathology, phenotype-genotype correlation, Cohort Studies, 0302 clinical medicine, C9orf72, amyotrophic lateral sclerosi, genetics, Amyotrophic lateral sclerosis, Age of Onset, amyotrophic lateral sclerosis, familial als, C9Orf72, 0303 health sciences, Sex Characteristics, DNA Repeat Expansion, Adult, Age of Onset, Aged, Amyotrophic Lateral Sclerosis, genetics/pathology, Cohort Studies, DNA Repeat Expansion, DNA, genetics, Female, Humans, Italy, Male, Middle Aged, Mutation, genetics, Parents, Pedigree, Phenotype, Proteins, genetics, Sex Characteristics, Survival Analysis, Middle Aged, 3. Good health, Pedigree, Settore MED/26 - NEUROLOGIA, Phenotype, Italy, Settore MED/26 - Neurologia, Female, Frontotemporal dementia, Adult, medicine.medical_specialty, SOD1, Biology, TARDBP, 03 medical and health sciences, Internal medicine, medicine, Humans, 030304 developmental biology, Aged, amyotrophic lateral sclerosis, familial ALS, C9ORF72 gene, phenotype–genotype correlation, C9orf72 Protein, Amyotrophic Lateral Sclerosis, genetics/pathology, Proteins, Original Articles, DNA, medicine.disease, Survival Analysis, Settore BIO/18 - Genetica, familial ALS, C9ORF72 gene, Mutation, Neurology (clinical), Age of onset, Trinucleotide repeat expansion, familial al, 030217 neurology & neurosurgery
Abstract

A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for 40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis–frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis–frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6–7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7–2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for 60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis. Keywords

Published
2012

27. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study

Author

Majounie, E1, Renton, Ae, Mok, K, Dopper, Eg, Waite, A, Rollinson, S, Chiò, A, Restagno, G, Nicolaou, N, Simon-Sanchez, J, van Swieten JC, Abramzon, Y, Johnson, Jo, Sendtner, M, Pamphlett, R, Orrell, Rw, Mead, S, Sidle, Kc, Houlden, H, Rohrer, Jd, Morrison, Ke, Pall, H, Talbot, K, Ansorge, O, Hernandez, Dg, Arepalli, S, Sabatelli, M, Mora, G, Corbo, M, Giannini, F, Calvo, A, Englund, E, Borghero, G, Floris, Gl, Remes, Am, Laaksovirta, H, Mccluskey, L, Trojanowski, Jq, Van Deerlin VM, Schellenberg, Gd, Nalls, Ma, Drory, Ve, Lu, Cs, Yeh, Th, Ishiura, H, Takahashi, Y, Tsuji, S, Le Ber, I, Brice, A, Drepper, C, Williams, N, Kirby, J, Shaw, P, Hardy, J, Tienari, Pj, Heutink, P, Morris, Hr, Pickering-Brown, S, Traynor, Bj, Adamson, G, Bayer, Aj, Beck, J, Callister, Jb, Blake, Dj, Blumen, Sc, Collinge, J, Dunckley, T, Ealing, J, East, S, Elman, L, Gerhard, A, Guerreiro, Rj, Gwinn, K, Halliwell, N, Hamdalla, Hh, Hewitt, C, Ince, P, Jablonka, S, James, C, Kent, L, Knock, Jc, Lynch, T, Mahoney, C, Mann, D, Neal, J, Norris, D, O'Dowd, S, Richardson, A, Rossor, M, Rothstein, J, Scholz, Sw, Snowden, J, Stephan, Da, Toulson, G, Turner, Mr, Warren, Jd, Young, K, Weng, Yh, Kuo, Hc, Lai, Sc, Huang, Cl, Camuzat, A, Entraingues, L, Guillot-Noël, Verpillat, P, Blanc, F, Camu, W, Clerget-Darpoux, F, Corcia, P, Couratier, P, Didic, M, Dubois, B, Duyckaerts, C, Guedj, E, Golfier, V, Habert, Mo, Hannequin, D, Lacomblez, L, Meininger, V, Salachas, F, Levy, R, Michel, Bf, Pasquier, F, Puel, M, Thomas-Anterion, C, Sellal, F, Vercelletto, M, Moglia, C, Cammarosano, S, Canosa, A, Gallo, S, Brunetti, M, Ossola, I, Marinou, K, Papetti, L, Pisano, F, Pinter, Gl, Conte, A, Luigetti, M, Zollino, M, Lattante, S, Marangi, G, la Bella, V, Spataro, R, Colletti, T, Battistini, S, Ricci, C, Caponnetto, C, Mancardi, G, Mandich, P, Salvi, F, Bartolomei, I, Mandrioli, J, Sola, P, Lunetta, C, Penco, S, Monsurrò, Mr, Tedeschi, G, Conforti, Fl, Gambardella, A, Quattrone, A, Volanti, P, Floris, G, Cannas, A, Piras, V, Marrosu, F, Marrosu, Mg, Murru, Mr, Pugliatti, M, Parish, Ld, Sotgiu, A, Solinas, G, Ulgheri, L, Ticca, A, Simone, I, Logroscino, G., Neurology, Erasmus MC other, The Chromosome 9-ALS/FTD Consortium, Human genetics, NCA - Neurodegeneration, Università degli studi di Torino (UNITO), Department of Clinical Genetics, Institute for Clinical Neurobiology, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), MRC Prion Unit, UCL Institute of neurology, UCL Institute of Neurology, UCL Institute of Neurology, Queen Square, London, Department of Neuroscience, Catholic University, Roma, Fondazione Maugeri, Department of Neuroscience, University of Siena, Siena, Department of Neurology, Chang Gung Memorial Hospital [Taipei] (CGMH), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Università degli studi di Torino = University of Turin (UNITO), Julius-Maximilians-Universität Würzburg (JMU), UCL Institute of Neurology, Queen Square [London], Università degli Studi di Siena = University of Siena (UNISI), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
MESH: Signal Transduction, Male, MESH: Vesicular Transport Proteins, MESH: Membrane Glycoproteins, MESH: DNA Repeat Expansion, MESH: Genotype, Cohort Studies, MESH: Protein Structure, Tertiary, MESH: Aged, 80 and over, MESH: Interferon Regulatory Factor-3, 0302 clinical medicine, C9orf72, MESH: Child, MESH: RNA, Small Interfering, 80 and over, genetics, Age of Onset, Child, MESH: Cohort Studies, MESH: Amyotrophic Lateral Sclerosis, MESH: Aged, Genetics, Aged, 80 and over, 0303 health sciences, MESH: Middle Aged, DNA Repeat Expansion, MESH: Toll-Like Receptor 4, Middle Aged, Penetrance, 3. Good health, Settore MED/26 - NEUROLOGIA, Neurology, MESH: Young Adult, MESH: HEK293 Cells, Child, Preschool, Frontotemporal Dementia, Female, Sample collection, Chromosomes, Human, Pair 9, MESH: Myeloid Differentiation Factor 88, Frontotemporal dementia, Human, Pair 9, Adult, MESH: Protein Transport, medicine.medical_specialty, Adolescent, Genotype, MESH: Age of Onset, MESH: RNA Interference, Clinical Neurology, MESH: Frontotemporal Dementia, MESH: Genetic Loci, TARDBP, Chromosomes, 03 medical and health sciences, Open Reading Frames, Young Adult, MESH: Cross-Sectional Studies, Internal medicine, medicine, MESH: Chemokine CCL5, Humans, ddc:610, Preschool, MESH: Adaptor Proteins, Signal Transducing, 030304 developmental biology, Aged, MESH: Adolescent, MESH: Humans, business.industry, MESH: Transfection, MESH: Child, Preschool, Haplotype, Amyotrophic Lateral Sclerosis, MESH: Adult, MESH: Adaptor Proteins, Vesicular Transport, MESH: Open Reading Frames, medicine.disease, MESH: Male, MESH: Cell Line, C9orf72 Protein, Cross-Sectional Studies, MESH: Endosomes, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), MESH: Lipopolysaccharides, MESH: Chromosomes, Human, Pair 9, business, Trinucleotide repeat expansion, MESH: Female, Adolescent, Adult, Age of Onset, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, genetics, Child, Child, Preschool, Chromosomes, genetics, Cohort Studies, Cross-Sectional Studies, DNA Repeat Expansion, genetics, Female, Frontotemporal Dementia, genetics, Genetic Loci, Genotype, Humans, Male, Middle Aged, Open Reading Frames, genetics, Young Adult, 030217 neurology & neurosurgery
Abstract

International audience; BACKGROUND: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). METHODS: We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. FINDINGS: In patients with sporadic ALS, we identified the repeat expansion in 236 (7*0%) of 3377 white individuals from the USA, Europe, and Australia, two (4*1%) of 49 black individuals from the USA, and six (8*3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39*3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6*0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24*8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. INTERPRETATION: A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

Published
2012
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28. CHCH10 mutations in an Italian cohort of familial and sporadic amyotrophic lateral sclerosis patients

Author

Chiò, A, Mora, G, Sabatelli, M, Caponnetto, C, Traynor, B. J, Johnson, J. O, Nalls, M. A, Calvo, A, Moglia, C, Borghero, G, Monsurrò, M. R, La Bella, V, Volanti, P, Simone, I, Salvi, F, Logullo, F. O, Nilo, R, Battistini, S, Mandrioli, J, Tanel, R, Murru, M. R, Mandich, P, Zollino, M, Conforti, F. L, Brunetti, M, Barberis, M, Restagno, G, Penco, S, Lunetta, C, Giannini, F, Ricci, C, Mancardi, G, Bartolomei, I, Corbo, M, Conte, A, Luigetti, M, Lattante, S, Marangi, G, Ossola, I, Logroscino, G, Tedeschi, G, Pugliatti, M, Pinter, G. L, Glynn, S, Gibbs, J. R, Cammarosano, S, Canosa, A, Manera, U, Bertuzzo, D, Ilardi, A, Marinou, K, Sideri, R, Pisano, F, Spataro, R, Colletti, T, Floris, G, Cannas, A, Piras, V, Marrosu, F, Marrosu, M. G, Parish, L. D, Ticca, A, Pirisi, A, Ortu, E, Cau, T. B, Loi, D, Traccis, S, Fini, N, Georgoulopoulou, E, Casale, F, Marrali, G, Fuda, G, Solamone, P, Maestri, E, Mazzei, R, Cristillo, V, Puddu, R, Costantino, E, Pani, C, Caredda, C, Origone, P, Mosca, L, Capasso, M, Turri, M, Petrucci, A, Tremolizzo, L, Santarelli, M., Chiò, A, Mora, G, Sabatelli, M, Caponnetto, C, Traynor, B, Johnson, J, Nalls, M, Calvo, A, Moglia, C, Borghero, G, Monsurrò, M, La Bella, V, Volanti, P, Simone, I, Salvi, F, Logullo, F, Nilo, R, Battistini, S, Mandrioli, J, Tanel, R, Murru, M, Mandich, P, Zollino, M, Conforti, F, Brunetti, M, Barberis, M, Restagno, G, Penco, S, Lunetta, C, Giannini, F, Ricci, C, Mancardi, G, Bartolomei, I, Corbo, M, Conte, A, Luigetti, M, Lattante, S, Marangi, G, Ossola, I, Logroscino, G, Tedeschi, G, Pugliatti, M, Pinter, G, Glynn, S, Gibbs, J, Cammarosano, S, Canosa, A, Manera, U, Bertuzzo, D, Ilardi, A, Marinou, K, Sideri, R, Pisano, F, Spataro, R, Colletti, T, Floris, G, Cannas, A, Piras, V, Marrosu, F, Marrosu, M, Parish, L, Ticca, A, Pirisi, A, Ortu, E, Cau, T, Loi, D, Traccis, S, Fini, N, Georgoulopoulou, E, Casale, F, Marrali, G, Fuda, G, Solamone, P, Maestri, E, Mazzei, R, Cristillo, V, Puddu, R, Costantino, E, Pani, C, Caredda, C, Origone, P, Mosca, L, Capasso, M, Turri, M, Petrucci, A, Tremolizzo, L, Santarelli, M, Chiò, Adriano, Mora, Gabriele, Sabatelli, Mario, Caponnetto, Claudia, Traynor, Bryan J., Johnson, Janel O., Nalls, Mike A., Calvo, Andrea, Moglia, Cristina, Borghero, Giuseppe, Monsurro', Maria Rosaria, La Bella, Vincenzo, Volanti, Paolo, Simone, Isabella, Salvi, Fabrizio, Logullo, Francesco O., Nilo, Riva, Battistini, Stefania, Mandrioli, Jessica, Tanel, Raffaella, Murru, Maria Rita, Mandich, Paola, Zollino, Marcella, Conforti, Francesca L., Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Penco, Silvana, Lunetta, Christian, Giannini, Fabio, Ricci, Claudia, Mancardi, Gianluigi, Bartolomei, Ilaria, Corbo, Massimo, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Ossola, Irene, Logroscino, Giancarlo, Tedeschi, Gioacchino, Pugliatti, Maura, Pinter, Giuseppe Lauria, Glynn, Shannon, Gibbs, J. Raphael, Cammarosano, Stefania, Canosa, Antonio, Manera, Umberto, Bertuzzo, Davide, Ilardi, Altonio, Marinou, Kalliopi, Sideri, Riccardo, Pisano, Fabrizio, Spataro, Rossella, Colletti, Tiziana, Floris, Gianluca, Cannas, Antonino, Piras, Valeria, Marrosu, Francesco, Marrosu, Maria Giovanna, Parish, Leslie D., Ticca, Anna, Pirisi, Angelo, Ortu, Enzo, Cau, Tea B., Loi, Daniela, Traccis, Sebastiano, Fini, Nicola, Georgoulopoulou, Eleni, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Solamone, Paolina, Maestri, Eleonora, Mazzei, Rosalucia, Cristillo, Viviana, Puddu, Roberta, Costantino, Emanuela, Pani, Carla, Caredda, Carla, Origone, Paola, Mosca, Lorena, Capasso, Margherita, Turri, Mara, Petrucci, Antonio, Tremolizzo, Luico, Santarelli, Marialaura, Chiò, A., Mora, G., Sabatelli, M., Caponnetto, C., Traynor, B., Johnson, J., Nalls, M., Calvo, A., Moglia, C., Borghero, G., Monsurrò, M., LA BELLA, V., Volanti, P., Simone, I., Salvi, F., Logullo, F., Nilo, R., Battistini, S., Mandrioli, J., Tanel, R., Murru, M., Mandich, P., Zollino, M., Conforti, F., Brunetti, M., Barberis, M., Restagno, G., Penco, S., Lunetta, C., Giannini, F., Ricci, C., Mancardi, G., Bartolomei, I., Corbo, M., Conte, A., Luigetti, M., Lattante, S., Marangi, G., Ossola, I., Logroscino, G., Tedeschi, G., Pugliatti, M., Pinter, G., Glynn, S., Gibbs, J., Cammarosano, S., Canosa, A., Manera, U., Bertuzzo, D., Ilardi, A., Marinou, K., Sideri, R., Pisano, F., Spataro, R., Colletti, T., Floris, G., Cannas, A., Piras, V., Marrosu, F., Marrosu, M., Parish, L., Ticca, A., Pirisi, A., Ortu, E., Cau, T., Loi, D., Traccis, S., Fini, N., Georgoulopoulou, E., Casale, F., Marrali, G., Fuda, G., Solamone, P., Maestri, E., Mazzei, R., Cristillo, V., Puddu, R., Costantino, E., Pani, C., Caredda, C., Origone, P., Mosca, L., Capasso, M., Turri, M., Petrucci, A., Tremolizzo, L., and Santarelli, M.

Subjects
Male, Aging, Pediatrics, medicine.medical_specialty, Pathology, Amyotrophic lateral sclerosis, CHCHD10, Familial, Sporadic, Aged, Amyotrophic Lateral Sclerosis, Cohort Studies, Female, Frontotemporal Dementia, Genetic Predisposition to Disease, Humans, Italy, Middle Aged, Mitochondrial Proteins, Genetic Association Studies, Mutation, Genetic Association Studie, Disease, Settore MED/03 - GENETICA MEDICA, medicine.disease_cause, Exon, mental disorders, medicine, Mitochondrial Protein, Dementia, Neurology (clinical), Neuroscience (all), Developmental Biology, Geriatrics and Gerontology, Amyotrophic lateral sclerosi, business.industry, General Neuroscience, medicine.disease, 3. Good health, Cohort, Cohort Studie, business, Human, Frontotemporal dementia, Cohort study
Abstract

Mutations in CHCHD10 have recently been described as a cause of frontotemporal dementia (FTD) comorbid with amyotrophic lateral sclerosis (ALS). The aim of this study was to assess the frequency and clinical characteristics of CHCHD10 mutations in Italian patients diagnosed with familial (n= 64) and apparently sporadic ALS (n= 224). Three apparently sporadic patients were found to carry c.100C>T (p.Pro34Ser) heterozygous variant in the exon 2 of CHCHD10. This mutation had been previously described in 2 unrelated French patients with FTD-ALS. However, our patients had a typical ALS, without evidence of FTD, cerebellar or extrapyramidal signs, or sensorineural deficits. We confirm that CHCHD10 mutations account for ~1% of Italian ALS patients and are a cause of disease in subjects without dementia or other atypical clinical signs.

Published
2015

29. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study

Author

Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, Chiò A, Restagno G, Nicolaou N, Simon Sanchez J, van Swieten JC, Abramzon Y, Johnson JO, Sendtner M, Pamphlett R, Orrell RW, Mead S, Sidle KC, Houlden H, Rohrer JD, Morrison KE, Pall H, Talbot K, Ansorge O, Chromosome 9 ALS/FTD Consortium, French research network on FTLD/FTLD/ALS, ITALSGEN Consortium, Adamson G, Bayer AJ, Beck J, Callister JB, Blake DJ, Blumen SC, Collinge J, Dunckley T, Ealing J, East S, Elman L, Gerhard A, Guerreiro RJ, Gwinn K, Halliwell N, Hamdalla HH, Hewitt C, Ince P, Jablonka S, James C, Kent L, Knock JC, Lynch T, Mahoney C, Mann D, Neal J, Norris D, O'Dowd S, Richardson A, Rossor M, Rothstein J, Scholz SW, Snowden J, Stephan DA, Toulson G, Turner MR, Warren JD, Young K, Weng YH, Kuo HC, Lai SC, Huang CL, Camuzat A, Entraingues L, Guillot Noël, Verpillat P, Blanc F, Camu W, Clerget Darpoux F, Corcia P, Couratier P, Didic M, Dubois B, Duyckaerts C, Guedj E, Golfier V, Habert MO, Hannequin D, Lacomblez L, Meininger V, Salachas F, Levy R, Michel BF, Pasquier F, Puel M, Thomas Anterion C, Sellal F, Vercelletto M, Moglia C, Cammarosano S, Canosa A, Gallo S, Brunetti M, Ossola I, Marinou K, Papetti L, Pisano F, Pinter GL, Conte A, Luigetti M, Zollino M, Lattante S, Marangi G, la Bella V, Spataro R, Colletti T, Battistini S, Ricci C, Caponnetto C, Mancardi G, Mandich P, Salvi F, Bartolomei I, Mandrioli J, Sola P, Lunetta C, Penco S, Conforti FL, Gambardella A, Quattrone A, Volanti P, Floris G, Cannas A, Piras V, Marrosu F, Marrosu MG, Murru MR, Pugliatti M, Parish LD, Sotgiu A, Solinas G, Ulgheri L, Ticca A, Simone I, Logroscino G, Hernandez DG, Arepalli S, Sabatelli M, Mora G, Corbo M, Giannini F, Calvo A, Englund E, Borghero G, Floris GL, Remes AM, Laaksovirta H, McCluskey L, Trojanowski JQ, Van Deerlin VM, Schellenberg GD, Nalls MA, Drory VE, Lu CS, Yeh TH, Ishiura H, Takahashi Y, Tsuji S, Le Ber I, Brice A, Drepper C, Williams N, Kirby J, Shaw P, Hardy J, Tienari PJ, Heutink P, Morris HR, Pickering Brown S, Traynor BJ, MONSURRO', Maria Rosaria, TEDESCHI, Gioacchino, Majounie, E, Renton, Ae, Mok, K, Dopper, Eg, Waite, A, Rollinson, S, Chiò, A, Restagno, G, Nicolaou, N, Simon Sanchez, J, van Swieten, Jc, Abramzon, Y, Johnson, Jo, Sendtner, M, Pamphlett, R, Orrell, Rw, Mead, S, Sidle, Kc, Houlden, H, Rohrer, Jd, Morrison, Ke, Pall, H, Talbot, K, Ansorge, O, Chromosome, 9 ALS/FTD Consortium, French research network on, Ftld/ftld/al, Italsgen, Consortium, Adamson, G, Bayer, Aj, Beck, J, Callister, Jb, Blake, Dj, Blumen, Sc, Collinge, J, Dunckley, T, Ealing, J, East, S, Elman, L, Gerhard, A, Guerreiro, Rj, Gwinn, K, Halliwell, N, Hamdalla, Hh, Hewitt, C, Ince, P, Jablonka, S, James, C, Kent, L, Knock, Jc, Lynch, T, Mahoney, C, Mann, D, Neal, J, Norris, D, O'Dowd, S, Richardson, A, Rossor, M, Rothstein, J, Scholz, Sw, Snowden, J, Stephan, Da, Toulson, G, Turner, Mr, Warren, Jd, Young, K, Weng, Yh, Kuo, Hc, Lai, Sc, Huang, Cl, Camuzat, A, Entraingues, L, Guillot, Noël, Verpillat, P, Blanc, F, Camu, W, Clerget Darpoux, F, Corcia, P, Couratier, P, Didic, M, Dubois, B, Duyckaerts, C, Guedj, E, Golfier, V, Habert, Mo, Hannequin, D, Lacomblez, L, Meininger, V, Salachas, F, Levy, R, Michel, Bf, Pasquier, F, Puel, M, Thomas Anterion, C, Sellal, F, Vercelletto, M, Moglia, C, Cammarosano, S, Canosa, A, Gallo, S, Brunetti, M, Ossola, I, Marinou, K, Papetti, L, Pisano, F, Pinter, Gl, Conte, A, Luigetti, M, Zollino, M, Lattante, S, Marangi, G, la Bella, V, Spataro, R, Colletti, T, Battistini, S, Ricci, C, Caponnetto, C, Mancardi, G, Mandich, P, Salvi, F, Bartolomei, I, Mandrioli, J, Sola, P, Lunetta, C, Penco, S, Monsurro', Maria Rosaria, Tedeschi, Gioacchino, Conforti, Fl, Gambardella, A, Quattrone, A, Volanti, P, Floris, G, Cannas, A, Piras, V, Marrosu, F, Marrosu, Mg, Murru, Mr, Pugliatti, M, Parish, Ld, Sotgiu, A, Solinas, G, Ulgheri, L, Ticca, A, Simone, I, Logroscino, G, Hernandez, Dg, Arepalli, S, Sabatelli, M, Mora, G, Corbo, M, Giannini, F, Calvo, A, Englund, E, Borghero, G, Floris, Gl, Remes, Am, Laaksovirta, H, Mccluskey, L, Trojanowski, Jq, Van Deerlin, Vm, Schellenberg, Gd, Nalls, Ma, Drory, Ve, Lu, C, Yeh, Th, Ishiura, H, Takahashi, Y, Tsuji, S, Le Ber, I, Brice, A, Drepper, C, Williams, N, Kirby, J, Shaw, P, Hardy, J, Tienari, Pj, Heutink, P, Morris, Hr, Pickering Brown, S, and Traynor, Bj

Published
2012

30. ATNX2 is not a regulatory gene in Italian amyotrophic lateral sclerosis patients with C9ORF72 GGGGCC expansion

Author

Chiò, A, Mora, G, Sabatelli, M, Caponnetto, C, Lunetta, C, Traynor, B, Johnson, J, Nalls, M, Calvo, A, Moglia, C, Borghero, G, Trojsi, F, La Bella, V, Volanti, P, Simone, I, Salvi, F, Logullo, F, Riva, N, Carrera, P, Giannini, F, Mandrioli, J, Tanel, R, Capasso, M, Tremolizzo, L, Battistini, S, Murru, M, Origone, P, Zollino, M, Penco, S, Mazzini, L, D'Alfonso, S, Restagno, G, Brunetti, M, Barberis, M, Conforti, F, Logroscino, G, Bartolomei, I, Mancardi, G, Mandich, P, Marinou, K, Sideri, R, Mosca, L, Lauria Pinter, G, Corbo, M, Fini, N, Fasano, A, Arosio, A, Ferrarese, C, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Bersano, A, Corrado, L, Bagarotti, A, Spataro, R, Colletti, T, Conte, A, Luigetti, M, Lattante, S, Marangi, G, Santarelli, M, Petrucci, A, Ricci, C, Benigni, M, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Ilardi, A, Manera, U, Bertuzzo, D, Pisano, F, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Ticca, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Ortu, E, Cau, T, Loi, D, TREMOLIZZO, LUCIO, AROSIO, ALESSANDRO, FERRARESE, CARLO, Loi, D., Chiò, A, Mora, G, Sabatelli, M, Caponnetto, C, Lunetta, C, Traynor, B, Johnson, J, Nalls, M, Calvo, A, Moglia, C, Borghero, G, Trojsi, F, La Bella, V, Volanti, P, Simone, I, Salvi, F, Logullo, F, Riva, N, Carrera, P, Giannini, F, Mandrioli, J, Tanel, R, Capasso, M, Tremolizzo, L, Battistini, S, Murru, M, Origone, P, Zollino, M, Penco, S, Mazzini, L, D'Alfonso, S, Restagno, G, Brunetti, M, Barberis, M, Conforti, F, Logroscino, G, Bartolomei, I, Mancardi, G, Mandich, P, Marinou, K, Sideri, R, Mosca, L, Lauria Pinter, G, Corbo, M, Fini, N, Fasano, A, Arosio, A, Ferrarese, C, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Bersano, A, Corrado, L, Bagarotti, A, Spataro, R, Colletti, T, Conte, A, Luigetti, M, Lattante, S, Marangi, G, Santarelli, M, Petrucci, A, Ricci, C, Benigni, M, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Ilardi, A, Manera, U, Bertuzzo, D, Pisano, F, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Ticca, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Ortu, E, Cau, T, Loi, D, TREMOLIZZO, LUCIO, AROSIO, ALESSANDRO, FERRARESE, CARLO, and Loi, D.

Abstract

There are indications that both familial amyotrophic lateral sclerosis (ALS) and sporadic ALS phenotype and prognosis are partly regulated by genetic and environmental factors, supporting the theory that ALS is a multifactorial disease. The aim of this article was to assess the role of ATXN2 intermediate length repeats in a large series of Italian and Sardinian ALS patients and controls carrying a pathogenetic C9ORF72 GGGGCC hexanucleotide repeat. A total of 1972 ALS cases were identified through the database of the Italian ALS Genetic consortium, a collaborative effort including 18 ALS centers throughout Italy. The study population included: (1) 276 Italian and 57 Sardinian ALS cases who carried the C9ORF72 expansion; (2) 1340 Italian and 299 Sardinian ALS cases not carrying the C9ORF72 expansion. A total of healthy 1043 controls were also assessed. Most Italian and Sardinian cases and controls were homozygous for 22/22 or 23/23 repeats or heterozygous for 22/23 repeats of the ATXN2 gene. ATXN2 intermediate length repeats alleles (≥28) were detected in 3 (0.6%) Italian ALS cases carrying the C9ORF72 expansion, in none of the Sardinian ALS cases carrying the expansion, in 60 (4.3%) Italian cases not carrying the expansion, and in 6 (2.0%) Sardinian ALS cases without C9ORF72 expansion. Intermediate length repeat alleles were found in 12 (1.5%) Italian controls and 1 (0.84%) Sardinian controls. Therefore, ALS patients with C9ORF72 expansion showed a lower frequency of ATXN2 polyQ intermediate length repeats than both controls (Italian cases, p = 0.137; Sardinian cases, p = 0.0001) and ALS patients without C9ORF72 expansion (Italian cases, p = 0.005; Sardinian cases, p = 0.178). In our large study on Italian and Sardinian ALS patients with C9ORF72 GGGGCC hexanucleotide repeat expansion, compared to age-, gender- and ethnic-matched controls, ATXN2 polyQ intermediate length does not represent a modifier of ALS risk, differently from non-C9ORF72 mutated patients.

Published
2016

31. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis

Author

Johnson, J. O., Pioro, E. P., Boehringer, A., Chia, R., Feit, H., Renton, A. E., Pliner, H. A., Abramzon, Y., Marangi, G., Winborn, B. J., Gibbs, J. R., Nalls, M. A., Morgan, S., Shoai, M., Hardy, J., Pittman, A., Orrell, R. W., Malaspina, A., Sidle, K. C., Fratta, P., Harms, M. B., Baloh, R. H., Pestronk, A., Weihl, C. C., Rogaeva, E., Zinman, L., Drory, V. E., Borghero, G., Mora, G., Calvo, A., Rothstein, J. D., Drepper, C., Sendtner, M., Singleton, A. B., Taylor, J. P., Cookson, M. R., Restagno, G., Sabatelli, M., Bowser, R., Chio`, A., Traynor, B. J., Moglia, C., Cammarosano, S., Canosa, A., Gallo, S., Brunetti, M., Ossola, I., Marinou, K., Papetti, L., Pisano, F., Pinter, G. L., Conte, A., Luigetti, M., Zollino, M., Lattante, S., la Bella, V., Spataro, R., Colletti, T., Battistini, S., Ricci, C., Caponnetto, C., Mancardi, G., Mandich, P., Salvi, F., Bartolomei, I., Mandrioli, J., Sola, P., Lunetta, C., Penco, S., Monsurro, M. R., Conforti, F. L., Tedeschi, G., Gambardella, A., Quattrone, A., Volanti, P., Floris, G., Cannas, A., Piras, V., Marrosu, F., Marrosu, M. G., Murru, M. R., Pugliatti, M., Parish, L. D., Sotgiu, A., Solinas, G., Ulgheri, L., Ticca, A., Simone, I., Logroscino, G., Pirisi, A., Johnson, JO, Pioro, EP, Boehringer, A, Chia, R, Feit, H5, Renton, AE, Pliner, HA, Abramzon, Y6, Marangi, G, Winborn, BJ, Gibbs, JR, Nalls, MA, Morgan, S, Shoai, M, Hardy, J, Pittman, A, Orrell, RW, Malaspina, A, Sidle, KC, Fratta, P, Harms, MB, Baloh, RH, Pestronk, A, Weihl, CC, Rogaeva, E, Zinman, L, Drory, VE, Borghero, G, Mora, G, Calvo, A, Rothstein, JD, ITALSGEN Consortium (including Cammarosano,S, Canosa, A, Moglia, C), Drepper, C, Sendtner, M, Singleton, AB, Taylor, JP, Cookson, MR, Restagno, G, Sabatelli, M, Bowser, R, Chiò, A, Traynor, BJ., Moglia, C., Canosa, A., Johnson, Jo, Pioro, Ep, Feit, H, Renton, Ae, Pliner, Ha, Abramzon, Y, Winborn, Bj, Gibbs, Jr, Nalls, Ma, Orrell, Rw, Sidle, Kc, Harms, Mb, Baloh, Rh, Weihl, Cc, Drory, Ve, Rothstein, Jd, Italsgen, Consortium, Among the, Collaborator, Monsurro', Maria Rosaria, Tedeschi, Gioacchino, Singleton, Ab, Taylor, Jp, Cookson, Mr, and Traynor, B. J.

Subjects
Male, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, genetics/pathology, Computational Biology, DNA Mutational Analysis, DNA-Binding Proteins, metabolism, Family Health, Female, Genetic Predisposition to Disease, genetics, Genotype, Humans, Male, Middle Aged, Muscle, Skeletal, metabolism/pathology, Mutation, genetics, Neurologic Examination, Nuclear Matrix-Associated Proteins, genetics/metabolism, RNA-Binding Proteins, genetics/metabolism, Spinal Cord, metabolism/pathology, DNA Mutational Analysis, genetics/metabolism, RNA-binding protein, Settore MED/03 - GENETICA MEDICA, medicine.disease_cause, 0302 clinical medicine, Nuclear Matrix-Associated Proteins, Genotype, 80 and over, genetics, Amyotrophic lateral sclerosis, Exome sequencing, Genetics, Aged, 80 and over, Neurologic Examination, 0303 health sciences, Mutation, General Neuroscience, RNA-Binding Proteins, Middle Aged, DNA-Binding Proteins, MATR3, medicine.anatomical_structure, Spinal Cord, familial amyotrophic lateral sclerosis, Muscle, Settore MED/26 - Neurologia, Female, Frontotemporal dementia, Article, 03 medical and health sciences, mental disorders, medicine, Humans, Genetic Predisposition to Disease, Muscle, Skeletal, 030304 developmental biology, Aged, Family Health, business.industry, Amyotrophic Lateral Sclerosis, genetics/pathology, RNA, Computational Biology, Spinal cord, medicine.disease, genetic, business, Neuroscience, metabolism, 030217 neurology & neurosurgery
Abstract

MATR3 is an RNA- and DNA-binding protein that interacts with TDP-43, a disease protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in ALS-affected spinal cords with and without MATR3 mutations. Our data provide more evidence supporting the role of aberrant RNA processing in motor neuron degeneration. © 2014 Nature America, Inc. All rights reserved.

Published
2014

32. ATXN2 is a modifier of phenotype in ALS patients of Sardinian ancestry

Author

Borghero, G, Pugliatti, M, Marrosu, F, Marrosu, Mg, Murru, Mr, Floris, G, Cannas, A, Parish, Ld, Cau, Tb, Loi, D, Ticca, A, Traccis, S, Manera, U, Canosa, A, Moglia, C, Calvo, A, Barberis, M, Brunetti, M, Renton, Ae, Nalls, Ma, Traynor, Bj, Restagno, G, Chiò, A, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Sabatelli, Mario (ORCID:0000-0001-6635-4985), Zollino, Marcella (ORCID:0000-0003-4871-9519), Luigetti, Marco (ORCID:0000-0001-7539-505X), Lattante, Serena (ORCID:0000-0003-2891-0340), Marangi, Giuseppe (ORCID:0000-0002-6898-8882), Borghero, G, Pugliatti, M, Marrosu, F, Marrosu, Mg, Murru, Mr, Floris, G, Cannas, A, Parish, Ld, Cau, Tb, Loi, D, Ticca, A, Traccis, S, Manera, U, Canosa, A, Moglia, C, Calvo, A, Barberis, M, Brunetti, M, Renton, Ae, Nalls, Ma, Traynor, Bj, Restagno, G, Chiò, A, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Sabatelli, Mario (ORCID:0000-0001-6635-4985), Zollino, Marcella (ORCID:0000-0003-4871-9519), Luigetti, Marco (ORCID:0000-0001-7539-505X), Lattante, Serena (ORCID:0000-0003-2891-0340), and Marangi, Giuseppe (ORCID:0000-0002-6898-8882)

Abstract

Intermediate-length CAG expansions (encoding 27-33 glutamines, polyQ) of the Ataxin2 (ATXN2) gene represent a risk factor for amyotrophic lateral sclerosis (ALS). Recently, it has been proposed that ≥31 CAG expansions may influence ALS phenotype. We assessed whether ATXN2 intermediate-length polyQ expansions influence ALS phenotype in a series of 375 patients of Sardinian ancestry. Controls were 247 neurologically healthy subjects, resident in the study area, age- and gender-matched to cases. The frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (4 patients vs. no control, p = 0.0001). All patients with ≥31 polyQ repeats had a spinal onset versus 73.3% of patients with <31 polyQ repeats. Patients with an increased number of polyQ repeats have a shorter survival than those with <31 repeats (1.2 vs. 4.2 years, p = 0.035). In this large series of ALS patients of Sardinian ancestry, we have found that ≥31 polyQ repeats of the ATXN2 gene influenced patients' phenotype, being associated to a spinal onset and a significantly shorter survival.

Published
2015

33. TBK1 is associated with ALS and ALS-FTD in Sardinian patients

Author

Borghero, G, Pugliatti, M, Marrosu, F, Marrosu, M, Murru, M, Floris, G, Cannas, A, Occhineri, P, Cau, T, Loi, D, Ticca, A, Traccis, S, Manera, U, Canosa, A, Moglia, C, Calvo, A, Barberis, M, Brunetti, M, Gibbs, J, Renton, A, Errichiello, E, Zoledziewska, M, Mulas, A, Qian, Y, Din, J, Pliner, H, Traynor, B, Chiò, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Capasso, M, Caponnetto, C, Mandich, P, Mancardi, G, Origone, P, Conforti, F, Vita, G, Messina, S, Russo, M, Mora, G, Marinou, K, Sideri, R, Lunetta, C, Penco, S, Mosca, L, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Tremolizzo, L, Ferrarese, C, Fini, N, Fasano, A, Monsurrò, M, Tedeschi, G, Trojsi, F, Piccirillo, G, Cristillo, V, Mazzini, L, D'Alfonso, S, Bersano, A, Corrado, L, Bagarotti, A, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Marangi, G, Santarelli, M, Petrucci, A, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Ilardi, A, Bertuzzo, D, Tanel, R, Pisano, F, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Pirisi, A, Parish, L, Ortu, E, Ortu, E., TREMOLIZZO, LUCIO, FERRARESE, CARLO, Borghero, G, Pugliatti, M, Marrosu, F, Marrosu, M, Murru, M, Floris, G, Cannas, A, Occhineri, P, Cau, T, Loi, D, Ticca, A, Traccis, S, Manera, U, Canosa, A, Moglia, C, Calvo, A, Barberis, M, Brunetti, M, Gibbs, J, Renton, A, Errichiello, E, Zoledziewska, M, Mulas, A, Qian, Y, Din, J, Pliner, H, Traynor, B, Chiò, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Capasso, M, Caponnetto, C, Mandich, P, Mancardi, G, Origone, P, Conforti, F, Vita, G, Messina, S, Russo, M, Mora, G, Marinou, K, Sideri, R, Lunetta, C, Penco, S, Mosca, L, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Tremolizzo, L, Ferrarese, C, Fini, N, Fasano, A, Monsurrò, M, Tedeschi, G, Trojsi, F, Piccirillo, G, Cristillo, V, Mazzini, L, D'Alfonso, S, Bersano, A, Corrado, L, Bagarotti, A, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Marangi, G, Santarelli, M, Petrucci, A, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Ilardi, A, Bertuzzo, D, Tanel, R, Pisano, F, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Pirisi, A, Parish, L, Ortu, E, Ortu, E., TREMOLIZZO, LUCIO, and FERRARESE, CARLO

Abstract

Recently, mutations in the TANK-binding kinase 1 (TBK1) gene were identified as a cause for amyotrophic lateral sclerosis (ALS) with or without comorbid frontotemporal dementia. We have assessed the frequency and clinical characteristics of TBK1 mutations in a cohort of ALS patients of Sardinian ancestry. Whole-exome sequencing was performed on Hiseq2000 platform (Illumina). Genome analysis Toolkit was used to align and to code variants according to Human Genome (UCSC hg19). Mutation was confirmed with Sanger sequence. In our screening of 186 Sardinian ALS cases, we found 3 (1.6%) patients carrying 3 distinct novel genetic variants: a nonsynonymous SNV c.1150C>T leading to a p.Arg384Thr change in exon 9; a nonsynonymous SNV c.1331G>A causes a p.Arg444Gln change in exon 11; and a frameshift deletion c.2070delG (p.Met690fs) at the exon 20 of the gene leading to a stop at 693 codon. The latter patients also carried missense mutation c.98C>T of the SQSTM1 gene causing a substitution of an arginine with a valine at the position 33 (p.Arg33Val). All variants were found to be deleterious according to in silico predictions. All cases were apparently sporadic and one of them showed frontotemporal dementia associated to ALS. These mutations were not found in 2 cohorts of 6780 ethnic-matched controls. We have found that TBK1 mutations account for 1.6% of Sardinian ALS cases. Our data support the notion that TBK1 is a novel ALS gene, providing important evidence complementary to the first descriptions.

Published
2015

36. ALS/FTD phenotype in two Sardinian families carrying both C9ORF72 and TARDBP mutations

Author

Chiò, A, Restagno, G, Brunetti, M, Ossola, I, Calvo, A, Canosa, A, Moglia, C, Floris, G, Tacconi, P, Marrosu, F, Marrosu, Mg, Murru, Mr, Majounie, E, Renton, Ae, Abramzon, Y, Pugliatti, Maura, Sotgiu, Ma, Traynor, Bj, Borghero, G, and Sardinials, Consortium

Subjects
Adult, Male, Mutation, Missense, Locus (genetics), Biology, TARDBP, Article, 03 medical and health sciences, 0302 clinical medicine, C9orf72, medicine, Missense mutation, Humans, genetics, Family, Amyotrophic lateral sclerosis, 030304 developmental biology, Genetics, 0303 health sciences, DNA Repeat Expansion, amyotrophic lateral sclerosis, frontotemporal dementia, C9orf72 Protein, Haplotype, Amyotrophic Lateral Sclerosis, C9orf72 Gene, Proteins, Middle Aged, medicine.disease, 3. Good health, Pedigree, DNA-Binding Proteins, Psychiatry and Mental health, Phenotype, Haplotypes, Italy, Frontotemporal Dementia, Surgery, Female, Neurology (clinical), Trinucleotide repeat expansion, 030217 neurology & neurosurgery
Abstract

Background In the isolated population of Sardinia, a Mediterranean island, ∼25% of ALS cases carry either a p.A382T mutation of the TARDBP gene or a GGGGCC hexanucleotide repeat expansion in the first intron of the C9ORF72 gene. Objective To describe the co-presence of two genetic mutations in two Sardinian ALS patients. Methods We identified two index ALS cases carrying both the p.A382T missense mutation of TARDBP gene and the hexanucleotide repeat expansion of C9ORF72 gene. Results The index case of Family A had bulbar ALS and frontemporal dementia (FTD) at 43. His father, who carried the hexanucleotide repeat expansion of C9ORF72 gene, had spinal ALS and FTD at 64 and his mother, who carried the TARDBP gene p.A382T missense mutation, had spinal ALS and FTD at 69. The index case of Family B developed spinal ALS without FTD at 35 and had a rapid course to respiratory failure. His parents are healthy at 62 and 63. The two patients share the known founder risk haplotypes across both the C9ORF72 9p21 locus and the TARDBP 1p36.22 locus. Conclusions Our data show that in rare neurodegenerative causing genes can co-exist within the same individuals and are associated with a more severe disease course.

Published
2012

37. C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population

Author

Sabatelli M, Conforti FL, Zollino M, Mora G, Monsurrò MR, Volanti P, Marinou K, Salvi F, Corbo M, Giannini F, Battistini S, Penco S, Lunetta C, Quattrone A, Gambardella A, Logroscino G, Simone I, Bartolomei I, Pisano F, Tedeschi G, Conte A, Spataro R, La Bella V, Caponnetto C, Mancardi G, Mandich P, Sola P, Mandrioli J, Renton AE, Majounie E, Abramzon Y, Marrosu F, Marrosu MG, Murru MR, Sotgiu MA, Pugliatti M, Rodolico C and ITALSGEN Consortium, Moglia C, Calvo A, Ossola I, Brunetti M, Traynor BJ, Borghero G, Restagno G, Chiò A.

Abstract

It has been recently reported that a large proportion of patients with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We have assessed 1757 Italian sporadic ALS cases, 133 from Sardinia, 101 from Sicily, and 1523 from mainland Italy. Sixty (3.7%) of 1624 mainland Italians and Sicilians and 9 (6.8%) of the 133 Sardinian sporadic ALS cases carried the pathogenic repeat expansion. None of the 619 regionally matched control samples (1238 chromosomes) carried the expansion. Twenty-five cases (36.2%) had behavioral FTD in addition to ALS. FTD or unspecified dementia was also detected in 19 pedigrees (27.5%) in first-degree relatives of ALS patients. Cases carrying the C9ORF72 hexanucleotide expansion survived 1 year less than cases who did not carry this mutation. In conclusion, we found that C9ORF72 hexanucleotide repeat expansions represents a sizeable proportion of apparent sporadic ALS in the Italian and Sardinian population, representing by far the most common mutation in Italy and the second most common in Sardinia.

Published
2012

38. Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72

Author

Chiò A, Borghero G, Restagno G, Mora G, Drepper C, Traynor BJ, Sendtner M, Brunetti M, Ossola I, Calvo A, Pugliatti M, Sotgiu MA, Murru MR, Marrosu MG, Marrosu F, Marinou K, Mandrioli J, Sola P, Caponnetto C, Mancardi G, Mandich P, La Bella V, Spataro R, Conte A, Monsurrò MR, Tedeschi G, Pisano F, Bartolomei I, Salvi F, Lauria Pinter G, Simone I, Logroscino G, Gambardella A, Quattrone A, Lunetta C, Volanti P, Zollino M, Penco S, Battistini S and ITALSGEN consortium, Renton AE, Majounie E, Abramzon Y, Conforti FL, Giannini F, Corbo M, Sabatelli M.

Abstract

A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for 40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis-frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis-frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6-7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7-2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for 60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis.

Published
2012

40. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy

Author

Brodie, M. J, Perucca, E, Ryvlin, P, Ben Menachem, E, Meencke, H. J, Van Landegem, W, Ossemann, M, Sadzot, B, Van Paesschen, W, Van Zandijcke, M, Hovorka, J, Marusic, P, Pazdera, L, Rektor, I, Stolcova, E, Tislerova, D, Kalviainen, R, Korpelainen, J, Peltola, J, Ranua, J, Geraud, G, Hirsch, E, Josien, E, Vercueil, L, Vespignani, H, Jeschke Rohrich, B, Keidel, M, Mattern, W, Ochs, G, Schmitz, B, Schumann, G, Balogh, A, Clemens, B, Czopf, J, Halasz, P, Rajna, P, Vecsei, L, Baruzzi, A, Beghi, A. E, Canevini, M. P, De Feo, M. R, Lamberti, P, Marciani, M. G, Marrosu, F, Mazza, Salvatore, Monaco, F, Mutani, R, Regesta, G, Zaccara, G, Drozdowski, W, Fryze, W, Jedrzejczak, J, Nowaki, P, Selmaj, K, Stelmasiak, Z, Wajgt, A, Bryer, A, Coetzee, C, Gardiner, J, Haug, P, Isaacs, M, Kelbe, C, Modi, G, Opperman, D, Shah, N, Wolberg, S, Arbizu, T, Forcadas, I, Macin Eiras, J. L, Martinez, M, Marti Masso, J. F, Molins, A, Serratosa, J. M, Borre, B, Kallen, K, Kumlien, E, Lindberger, M, Palm, R, Carpay, J. A, Sanders, E. A. C. M, Van Leusden, J. A, Vecht, C, Roberts, R. C, Smith, P, and Tidswell, P.

Subjects
business.industry, levetiracetam, oxcarbazepine, Carbamazepine, medicine.disease, law.invention, Epilepsy, Settore MED/26 - NEUROLOGIA, Tolerability, Randomized controlled trial, law, Anesthesia, Clinical endpoint, Medicine, epilepsy, Neurology (clinical), Levetiracetam, business, Adverse effect, Oxcarbazepine, medicine.drug
Abstract

Objective: We report the results of a prospective study of the efficacy and tolerability of levetiracetam, a new antiepileptic drug with a unique mechanism of action, in comparison with controlled-release carbamazepine as first treatment in newly diagnosed epilepsy. Methods: Adults with ≥2 partial or generalized tonic–clonic seizures in the previous year were randomly assigned to levetiracetam (500 mg twice daily, n = 288) or controlled-release carbamazepine (200 mg twice daily, n = 291) in a multicenter, double-blind, noninferiority, parallel-group trial. If a seizure occurred within 26 weeks of stabilization, dosage was increased incrementally to a maximum of levetiracetam 1,500 mg twice daily or carbamazepine 600 mg twice daily. Patients achieving the primary endpoint (6-month seizure freedom) continued on treatment for a further 6-month maintenance period. Results: At per-protocol analysis, 73.0% (56.6%) of patients randomized to levetiracetam and 72.8% (58.5%) receiving controlled-release carbamazepine were seizure free at the last evaluated dose (adjusted absolute difference 0.2%, 95% CI −7.8% to 8.2%) for ≥6 months (1 year). Of all patients achieving 6-month (1-year) remission, 80.1% (86.0%) in the levetiracetam group and 85.4% (89.3%) in the carbamazepine group did so at the lowest dose level. Withdrawal rates for adverse events were 14.4% with levetiracetam and 19.2% with carbamazepine. Conclusions: Levetiracetam and controlled-release carbamazepine produced equivalent seizure freedom rates in newly diagnosed epilepsy at optimal dosing in a setting mimicking clinical practice. This trial has confirmed in a randomized, double-blind setting previously uncontrolled observations that most people with epilepsy will respond to their first-ever antiepileptic drug at low dosage.

Published
2007

44. Localizzazione MEG delle frequenze lente (ALFMA) nei tumori cerebrali epilettogeni

Author

Puligheddu, M., Baayen, H. C., De Jongh, A., De Munck, J. C., Stam, C. J., Van Cappellen Van Walsum, A. M., Heimans, J. J., Kasteleins-Nolst Trenité, D. G.A., Berendse, H. W., Jonkman, J. J., Vandertop, W. P., Marrosu, F., Neurosurgery, Amsterdam Neuroscience - Systems & Network Neuroscience, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, Radiology and nuclear medicine, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Neurovascular Disorders, Neurology, Amsterdam Neuroscience - Neurodegeneration, CCA - Cancer Treatment and quality of life, and CCA - Cancer Treatment and Quality of Life

Subjects
Epilepsy, Brain Tumors, Magnetoencephalography (MEG), Abnormal Low Frequency Magnetic Activity (ALFMA)
Abstract

Cortical brain tumors are frequently accompanied by epilepsy correlated with alterations of rhythmic brain activities such as specific spiking trains and slow waves. Given that, frankly epileptic spikes cannot be detected in a large part of epileptogenic tumors unless undertaking long monitoring EEG recordings. Moreover, considering the relevance in monitoring the epileptogenic potential of the brain tumors in a surgical setting, we investigated, in the present study the possibility that abnormal low frequency magnetic activity (ALFMA), recorded by Magnetoencephalography (MEG) can be of some help in mapping epileptogenic brain tumors, even in absence of clear-cut epileptogenic spiking activity.

Published
2003

45. C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population

Author

Sabatelli, Mario, Conforti, Fl, Zollino, Marcella, Mora, G, Monsurrò, Mr, Volanti, P, Marinou, K, Salvi, F, Corbo, M, Giannini, F, Battistini, S, Penco, S, Lunetta, C, Quattrone, A, Gambardella, A, Logroscino, G, Simone, I, Bartolomei, I, Pisano, F, Tedeschi, G, Conte, Amelia, Spataro, R, La Bella, V, Caponnetto, C, Mancardi, G, Mandich, P, Sola, P, Mandrioli, J, Renton, Ae, Majounie, E, Abramzon, Y, Marrosu, F, Marrosu, Mg, Murru, Mr, Sotgiu, Ma, Pugliatti, M, Rodolico, C, Moglia, C, Calvo, A, Ossola, I, Brunetti, M, Traynor, Bj, Borghero, G, Restagno, G, Chiò, A., Sabatelli, Mario (ORCID:0000-0001-6635-4985), Zollino, Marcella (ORCID:0000-0003-4871-9519), Sabatelli, Mario, Conforti, Fl, Zollino, Marcella, Mora, G, Monsurrò, Mr, Volanti, P, Marinou, K, Salvi, F, Corbo, M, Giannini, F, Battistini, S, Penco, S, Lunetta, C, Quattrone, A, Gambardella, A, Logroscino, G, Simone, I, Bartolomei, I, Pisano, F, Tedeschi, G, Conte, Amelia, Spataro, R, La Bella, V, Caponnetto, C, Mancardi, G, Mandich, P, Sola, P, Mandrioli, J, Renton, Ae, Majounie, E, Abramzon, Y, Marrosu, F, Marrosu, Mg, Murru, Mr, Sotgiu, Ma, Pugliatti, M, Rodolico, C, Moglia, C, Calvo, A, Ossola, I, Brunetti, M, Traynor, Bj, Borghero, G, Restagno, G, Chiò, A., Sabatelli, Mario (ORCID:0000-0001-6635-4985), and Zollino, Marcella (ORCID:0000-0003-4871-9519)

Abstract

It has been recently reported that a large proportion of patients with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We have assessed 1757 Italian sporadic ALS cases, 133 from Sardinia, 101 from Sicily, and 1523 from mainland Italy. Sixty (3.7%) of 1624 mainland Italians and Sicilians and 9 (6.8%) of the 133 Sardinian sporadic ALS cases carried the pathogenic repeat expansion. None of the 619 regionally matched control samples (1238 chromosomes) carried the expansion. Twenty-five cases (36.2%) had behavioral FTD in addition to ALS. FTD or unspecified dementia was also detected in 19 pedigrees (27.5%) in first-degree relatives of ALS patients. Cases carrying the C9ORF72 hexanucleotide expansion survived 1 year less than cases who did not carry this mutation. In conclusion, we found that C9ORF72 hexanucleotide repeat expansions represents a sizeable proportion of apparent sporadic ALS in the Italian and Sardinian population, representing by far the most common mutation in Italy and the second most common in Sardinia.

Published
2012

46. Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72

Author

Chiò, A, Borghero, G, Restagno, G, Mora, G, Drepper, C, Traynor, Bj, Sendtner, M, Brunetti, M, Ossola, I, Calvo, A, Pugliatti, M, Sotgiu, Ma, Murru, Mr, Marrosu, Mg, Marrosu, F, Marinou, K, Mandrioli, J, Sola, P, Caponnetto, C, Mancardi, G, Mandich, P, La Bella, V, Spataro, R, Conte, Amelia, Monsurrò, Mr, Tedeschi, G, Pisano, F, Bartolomei, I, Salvi, F, Lauria Pinter, G, Simone, I, Logroscino, G, Gambardella, A, Quattrone, A, Lunetta, C, Volanti, P, Zollino, Marcella, Penco, S, Battistini, S, Renton, Ae, Majounie, E, Abramzon, Y, Conforti, Fl, Giannini, F, Corbo, Massimo, Sabatelli, Mario, Zollino, Marcella (ORCID:0000-0003-4871-9519), Sabatelli, Mario (ORCID:0000-0001-6635-4985), Chiò, A, Borghero, G, Restagno, G, Mora, G, Drepper, C, Traynor, Bj, Sendtner, M, Brunetti, M, Ossola, I, Calvo, A, Pugliatti, M, Sotgiu, Ma, Murru, Mr, Marrosu, Mg, Marrosu, F, Marinou, K, Mandrioli, J, Sola, P, Caponnetto, C, Mancardi, G, Mandich, P, La Bella, V, Spataro, R, Conte, Amelia, Monsurrò, Mr, Tedeschi, G, Pisano, F, Bartolomei, I, Salvi, F, Lauria Pinter, G, Simone, I, Logroscino, G, Gambardella, A, Quattrone, A, Lunetta, C, Volanti, P, Zollino, Marcella, Penco, S, Battistini, S, Renton, Ae, Majounie, E, Abramzon, Y, Conforti, Fl, Giannini, F, Corbo, Massimo, Sabatelli, Mario, Zollino, Marcella (ORCID:0000-0003-4871-9519), and Sabatelli, Mario (ORCID:0000-0001-6635-4985)

Abstract

A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for ~40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis-frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis-frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median

Published
2012

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