Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis
Authors
Johnson, Janel OChia, Ruth
Miller, Danny E
Li, Rachel
Kumaran, Ravindran
Abramzon, Yevgeniya
Alahmady, Nada
Renton, Alan E
Topp, Simon D
Gibbs, J Raphael
Cookson, Mark R
Sabir, Marya S
Dalgard, Clifton L
Troakes, Claire
Jones, Ashley R
Shatunov, Aleksey
Iacoangeli, Alfredo
Al Khleifat, Ahmad
Ticozzi, Nicola
Silani, Vincenzo
Gellera, Cinzia
Blair, Ian P
Dobson-Stone, Carol
Kwok, John B
Bonkowski, Emily S
Palvadeau, Robin
Tienari, Pentti J
Morrison, Karen E
Shaw, Pamela J
Al-Chalabi, Ammar
Brown, Robert H
Calvo, Andrea
Mora, Gabriele
Al-Saif, Hind
Gotkine, Marc
Leigh, Fawn
Chang, Irene J
Perlman, Seth J
Glass, Ian
Scott, Anna I
Shaw, Christopher E
Basak, A Nazli
Landers, John E
Chiò, Adriano
Crawford, Thomas O
Smith, Bradley N
Traynor, Bryan J
Smith, Bradley N
Ticozzi, Nicola
Fallini, Claudia
Gkazi, Athina Soragia
Topp, Simon D
Scotter, Emma L
Kenna, Kevin P
Keagle, Pamela
Tiloca, Cinzia
Vance, Caroline
Troakes, Claire
Colombrita, Claudia
King, Andrew
Pensato, Viviana
Castellotti, Barbara
Baas, Frank
Ten Asbroek, Anneloor L M A
McKenna-Yasek, Diane
McLaughlin, Russell L
Polak, Meraida
Asress, Seneshaw
Esteban-Pérez, Jesús
Stevic, Zorica
D'Alfonso, Sandra
Mazzini, Letizia
Comi, Giacomo P
Del Bo, Roberto
Ceroni, Mauro
Gagliardi, Stella
Querin, Giorgia
Bertolin, Cinzia
Van Rheenen, Wouter
Rademakers, Rosa
van Blitterswijk, Marka
Lauria, Giuseppe
Duga, Stefano
Corti, Stefania
Cereda, Cristina
Corrado, Lucia
Sorarù, Gianni
Williams, Kelly L
Nicholson, Garth A
Blair, Ian P
Leblond-Manry, Claire
Rouleau, Guy A
Hardiman, Orla
Morrison, Karen E
Veldink, Jan H
van den Berg, Leonard H
Al-Chalabi, Ammar
Pall, Hardev
Shaw, Pamela J
Turner, Martin R
Talbot, Kevin
Taroni, Franco
García-Redondo, Alberto
Wu, Zheyang
Glass, Jonathan D
Gellera, Cinzia
Ratti, Antonia
Brown, Robert H
Silani, Vincenzo
Shaw, Christopher E
Landers, John E
Dalgard, Clifton L
Adeleye, Adelani
Soltis, Anthony R
Alba, Camille
Viollet, Coralie
Bacikova, Dagmar
Hupalo, Daniel N
Sukumar, Gauthaman
Pollard, Harvey B
Wilkerson, Matthew D
Martinez, Elisa McGrath
Abramzon, Yevgeniya
Ahmed, Sarah
Arepalli, Sampath
Baloh, Robert H
Bowser, Robert
Brady, Christopher B
Brice, Alexis
Broach, James
Campbell, Roy H
Camu, William
Chia, Ruth
Cooper-Knock, John
Ding, Jinhui
Drepper, Carsten
Drory, Vivian E
Dunckley, Travis L
Eicher, John D
England, Bryce K
Faghri, Faraz
Feldman, Eva
Floeter, Mary Kay
Fratta, Pietro
Geiger, Joshua T
Gerhard, Glenn
Gibbs, J Raphael
Gibson, Summer B
Glass, Jonathan D
Hardy, John
Harms, Matthew B
Heiman-Patterson, Terry D
Hernandez, Dena G
Jansson, Lilja
Kirby, Janine
Kowall, Neil W
Laaksovirta, Hannu
Landeck, Natalie
Landi, Francesco
Le Ber, Isabelle
Lumbroso, Serge
MacGowan, Daniel J L
Maragakis, Nicholas J
Mora, Gabriele
Mouzat, Kevin
Murphy, Natalie A
Myllykangas, Liisa
Nalls, Mike A
Orrell, Richard W
Ostrow, Lyle W
Pamphlett, Roger
Pickering-Brown, Stuart
Pioro, Erik P
Pletnikova, Olga
Pliner, Hannah A
Pulst, Stefan M
Ravits, John M
Renton, Alan E
Rivera, Alberto
Robberecht, Wim
Rogaeva, Ekaterina
Rollinson, Sara
Rothstein, Jeffrey D
Scholz, Sonja W
Sendtner, Michael
Shaw, Pamela J
Sidle, Katie C
Simmons, Zachary
Singleton, Andrew B
Smith, Nathan
Stone, David J
Tienari, Pentti J
Troncoso, Juan C
Valori, Miko
Van Damme, Philip
Van Deerlin, Vivianna M
Van Den Bosch, Ludo
Zinman, Lorne
Landers, John E
Chiò, Adriano
Traynor, Bryan J
Angelocola, Stefania M
Ausiello, Francesco P
Barberis, Marco
Bartolomei, Ilaria
Battistini, Stefania
Bersano, Enrica
Bisogni, Giulia
Borghero, Giuseppe
Brunetti, Maura
Cabona, Corrado
Calvo, Andrea
Canale, Fabrizio
Canosa, Antonio
Cantisani, Teresa A
Capasso, Margherita
Caponnetto, Claudia
Cardinali, Patrizio
Carrera, Paola
Casale, Federico
Chiò, Adriano
Colletti, Tiziana
Conforti, Francesca L
Conte, Amelia
Conti, Elisa
Corbo, Massimo
Cuccu, Stefania
Dalla Bella, Eleonora
D'Errico, Eustachio
DeMarco, Giovanni
Dubbioso, Raffaele
Ferrarese, Carlo
Ferraro, Pilar M
Filippi, Massimo
Fini, Nicola
Floris, Gianluca
Fuda, Giuseppe
Gallone, Salvatore
Gianferrari, Giulia
Giannini, Fabio
Grassano, Maurizio
Greco, Lucia
Iazzolino, Barbara
Introna, Alessandro
La Bella, Vincenzo
Lattante, Serena
Lauria, Giuseppe
Liguori, Rocco
Logroscino, Giancarlo
Logullo, Francesco O
Lunetta, Christian
Mandich, Paola
Mandrioli, Jessica
Manera, Umberto
Manganelli, Fiore
Marangi, Giuseppe
Marinou, Kalliopi
Marrosu, Maria Giovanna
Martinelli, Ilaria
Messina, Sonia
Moglia, Cristina
Mora, Gabriele
Mosca, Lorena
Murru, Maria R
Origone, Paola
Passaniti, Carla
Petrelli, Cristina
Petrucci, Antonio
Pozzi, Susanna
Pugliatti, Maura
Quattrini, Angelo
Ricci, Claudia
Riolo, Giulia
Riva, Nilo
Russo, Massimo
Sabatelli, Mario
Salamone, Paolina
Salivetto, Marco
Salvi, Fabrizio
Santarelli, Marialuisa
Sbaiz, Luca
Sideri, Riccardo
Simone, Isabella
Simonini, Cecilia
Spataro, Rossella
Tanel, Raffaella
Tedeschi, Gioacchino
Ticca, Anna
Torriello, Antonella
Tranquilli, Stefania
Tremolizzo, Lucio
Trojsi, Francesca
Vasta, Rosario
Vacchiano, Veria
Vita, Giuseppe
Volanti, Paolo
Zollino, Marcella
Zucchi, Elisabetta
UMass Chan Affiliations
NeurologyDocument Type
Journal ArticlePublication Date
2021-08-30
Metadata
Show full item recordAbstract
Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective: To identify the genetic variants associated with juvenile ALS. Design, setting, and participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. Main outcomes and measures: De novo variants present only in the index case and not in unaffected family members. Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. Conclusions and relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.Source
Johnson JO, Chia R, Miller DE, Li R, Kumaran R, Abramzon Y, Alahmady N, Renton AE, Topp SD, Gibbs JR, Cookson MR, Sabir MS, Dalgard CL, Troakes C, Jones AR, Shatunov A, Iacoangeli A, Al Khleifat A, Ticozzi N, Silani V, Gellera C, Blair IP, Dobson-Stone C, Kwok JB, Bonkowski ES, Palvadeau R, Tienari PJ, Morrison KE, Shaw PJ, Al-Chalabi A, Brown RH Jr, Calvo A, Mora G, Al-Saif H, Gotkine M, Leigh F, Chang IJ, Perlman SJ, Glass I, Scott AI, Shaw CE, Basak AN, Landers JE, Chiò A, Crawford TO, Smith BN, Traynor BJ; FALS Sequencing Consortium; American Genome Center; International ALS Genomics Consortium; and ITALSGEN Consortium; Smith BN, Ticozzi N, Fallini C, Gkazi AS, Topp SD, Scotter EL, Kenna KP, Keagle P, Tiloca C, Vance C, Troakes C, Colombrita C, King A, Pensato V, Castellotti B, Baas F, Ten Asbroek ALMA, McKenna-Yasek D, McLaughlin RL, Polak M, Asress S, Esteban-Pérez J, Stevic Z, D'Alfonso S, Mazzini L, Comi GP, Del Bo R, Ceroni M, Gagliardi S, Querin G, Bertolin C, van Rheenen W, Rademakers R, van Blitterswijk M, Lauria G, Duga S, Corti S, Cereda C, Corrado L, Sorarù G, Williams KL, Nicholson GA, Blair IP, Leblond-Manry C, Rouleau GA, Hardiman O, Morrison KE, Veldink JH, van den Berg LH, Al-Chalabi A, Pall H, Shaw PJ, Turner MR, Talbot K, Taroni F, García-Redondo A, Wu Z, Glass JD, Gellera C, Ratti A, Brown RH Jr, Silani V, Shaw CE, Landers JE, Dalgard CL, Adeleye A, Soltis AR, Alba C, Viollet C, Bacikova D, Hupalo DN, Sukumar G, Pollard HB, Wilkerson MD, Martinez EM, Abramzon Y, Ahmed S, Arepalli S, Baloh RH, Bowser R, Brady CB, Brice A, Broach J, Campbell RH, Camu W, Chia R, Cooper-Knock J, Ding J, Drepper C, Drory VE, Dunckley TL, Eicher JD, England BK, Faghri F, Feldman E, Floeter MK, Fratta P, Geiger JT, Gerhard G, Gibbs JR, Gibson SB, Glass JD, Hardy J, Harms MB, Heiman-Patterson TD, Hernandez DG, Jansson L, Kirby J, Kowall NW, Laaksovirta H, Landeck N, Landi F, Le Ber I, Lumbroso S, MacGowan DJL, Maragakis NJ, Mora G, Mouzat K, Murphy NA, Myllykangas L, Nalls MA, Orrell RW, Ostrow LW, Pamphlett R, Pickering-Brown S, Pioro EP, Pletnikova O, Pliner HA, Pulst SM, Ravits JM, Renton AE, Rivera A, Robberecht W, Rogaeva E, Rollinson S, Rothstein JD, Scholz SW, Sendtner M, Shaw PJ, Sidle KC, Simmons Z, Singleton AB, Smith N, Stone DJ, Tienari PJ, Troncoso JC, Valori M, Van Damme P, Van Deerlin VM, Van Den Bosch L, Zinman L, Landers JE, Chiò A, Traynor BJ, Angelocola SM, Ausiello FP, Barberis M, Bartolomei I, Battistini S, Bersano E, Bisogni G, Borghero G, Brunetti M, Cabona C, Calvo A, Canale F, Canosa A, Cantisani TA, Capasso M, Caponnetto C, Cardinali P, Carrera P, Casale F, Chiò A, Colletti T, Conforti FL, Conte A, Conti E, Corbo M, Cuccu S, Dalla Bella E, D'Errico E, DeMarco G, Dubbioso R, Ferrarese C, Ferraro PM, Filippi M, Fini N, Floris G, Fuda G, Gallone S, Gianferrari G, Giannini F, Grassano M, Greco L, Iazzolino B, Introna A, La Bella V, Lattante S, Lauria G, Liguori R, Logroscino G, Logullo FO, Lunetta C, Mandich P, Mandrioli J, Manera U, Manganelli F, Marangi G, Marinou K, Marrosu MG, Martinelli I, Messina S, Moglia C, Mora G, Mosca L, Murru MR, Origone P, Passaniti C, Petrelli C, Petrucci A, Pozzi S, Pugliatti M, Quattrini A, Ricci C, Riolo G, Riva N, Russo M, Sabatelli M, Salamone P, Salivetto M, Salvi F, Santarelli M, Sbaiz L, Sideri R, Simone I, Simonini C, Spataro R, Tanel R, Tedeschi G, Ticca A, Torriello A, Tranquilli S, Tremolizzo L, Trojsi F, Vasta R, Vacchiano V, Vita G, Volanti P, Zollino M, Zucchi E. Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis. JAMA Neurol. 2021 Oct 1;78(10):1236-1248. doi: 10.1001/jamaneurol.2021.2598. PMID: 34459874; PMCID: PMC8406220.DOI
10.1001/jamaneurol.2021.2598Permanent Link to this Item
http://hdl.handle.net/20.500.14038/51663PubMed ID
34459874ae974a485f413a2113503eed53cd6c53
10.1001/jamaneurol.2021.2598
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