Association of Variants in the SPTLC1 Gene with Juvenile Amyotrophic Lateral Sclerosis

Janel O. Johnson; Ruth Chia; Danny E. Miller; Rachel Li; Ravindran Kumaran; Yevgeniya Abramzon; Nada Alahmady; Alan E. Renton; Simon D. Topp; J. Raphael Gibbs; Mark R. Cookson; Marya S. Sabir; Clifton L. Dalgard; Claire Troakes; Ashley R. Jones; Aleksey Shatunov; Alfredo Iacoangeli; Ahmad Al Khleifat; Nicola Ticozzi; Vincenzo Silani; Cinzia Gellera; Ian P. Blair; Carol Dobson-Stone; John B. Kwok; Emily S. Bonkowski; Robin Palvadeau; Pentti J. Tienari; Karen E. Morrison; Pamela J. Shaw; Ammar Al-Chalabi; Robert H. Brown; Andrea Calvo; Gabriele Mora; Hind Al-Saif; Marc Gotkine; Fawn Leigh; Irene J. Chang; Seth J. Perlman; Ian Glass; Anna I. Scott; Christopher E. Shaw; A. Nazli Basak; John E. Landers; Adriano Chiò; Thomas O. Crawford; Bradley N. Smith; Bryan J. Traynor; Bradley N. Smith; Claudia Fallini; Athina Soragia Gkazi; Simon D. Topp; Emma L. Scotter; Kevin P. Kenna; Pamela Keagle; Cinzia Tiloca; Caroline Vance; Claire Troakes; Claudia Colombrita; Andrew King; Viviana Pensato; Barbara Castellotti; Frank Baas; Anneloor L.M.A. Ten Asbroek; Diane McKenna-Yasek; Russell L. McLaughlin; Meraida Polak; Seneshaw Asress; Jesús Esteban-Pérez; Zorica Stevic; Sandra D'Alfonso; Letizia Mazzini; Giacomo P. Comi; Roberto Del Bo; Mauro Ceroni; Stella Gagliardi; Giorgia Querin; Cinzia Bertolin; Wouter Van Rheenen; Rosa Rademakers; Marka Van Blitterswijk; Giuseppe Lauria; Stefano Duga; Stefania Corti; Cristina Cereda; Lucia Corrado; Gianni Sorarù; Kelly L. Williams; Garth A. Nicholson; Ian P. Blair; Claire Leblond-Manry; Guy A. Rouleau; Orla Hardiman; Karen E. Morrison; Jan H. Veldink; Leonard H. Van Den Berg; Hardev Pall; Martin R. Turner; Kevin Talbot; Franco Taroni; Alberto García-Redondo; Zheyang Wu; Jonathan D. Glass; Cinzia Gellera; Antonia Ratti; Robert H. Brown; John E. Landers; Clifton L. Dalgard; Adelani Adeleye; Anthony R. Soltis; Camille Alba; Coralie Viollet; Dagmar Bacikova; Daniel N. Hupalo; Gauthaman Sukumar; Harvey B. Pollard; Matthew D. Wilkerson; Elisa Mc Grath Martinez; Yevgeniya Abramzon; Sarah Ahmed; Sampath Arepalli; Robert H. Baloh; Robert Bowser; Christopher B. Brady; Alexis Brice; James Broach; Roy H. Campbell; William Camu; John Cooper-Knock; Jinhui Ding; Carsten Drepper; Vivian E. Drory; Travis L. Dunckley; John D. Eicher; Bryce K. England; Faraz Faghri; Eva Feldman; Mary Kay Floeter; Pietro Fratta; Joshua T. Geiger; Glenn Gerhard; J. Raphael Gibbs; Summer B. Gibson; Jonathan D. Glass; John Hardy; Matthew B. Harms; Terry D. Heiman-Patterson; Dena G. Hernandez; Lilja Jansson; Janine Kirby; Neil W. Kowall; Hannu Laaksovirta; Natalie Landeck; Francesco Landi; Isabelle Le Ber; Serge Lumbroso; Daniel J.L. Macgowan; Nicholas J. Maragakis; Kevin Mouzat; Natalie A. Murphy; Liisa Myllykangas; Mike A. Nalls; Richard W. Orrell; Lyle W. Ostrow; Roger Pamphlett; Stuart Pickering-Brown; Erik P. Pioro; Olga Pletnikova; Hannah A. Pliner; Stefan M. Pulst; John M. Ravits; Alan E. Renton; Alberto Rivera; Wim Robberecht; Ekaterina Rogaeva; Sara Rollinson; Jeffrey D. Rothstein; Sonja W. Scholz; Michael Sendtner; Katie C. Sidle; Zachary Simmons; Andrew B. Singleton; Nathan Smith; David J. Stone; Pentti J. Tienari; Juan C. Troncoso; Miko Valori; Philip Van Damme; Vivianna M. Van Deerlin; Ludo Van Den Bosch; Lorne Zinman; John E. Landers; Adriano Chiò; Bryan J. Traynor; Stefania M. Angelocola; Francesco P. Ausiello; Marco Barberis; Ilaria Bartolomei; Stefania Battistini; Enrica Bersano; Giulia Bisogni; Giuseppe Borghero; Maura Brunetti; Corrado Cabona; Andrea Calvo; Fabrizio Canale; Antonio Canosa; Teresa A. Cantisani; Margherita Capasso; Claudia Caponnetto; Patrizio Cardinali; Paola Carrera; Federico Casale; Adriano Chiò; Tiziana Colletti; Francesca L. Conforti; Amelia Conte; Elisa Conti; Massimo Corbo; Stefania Cuccu; Eleonora Dalla Bella; Eustachio D'Errico; Giovanni Demarco; Raffaele Dubbioso; Carlo Ferrarese; Pilar M. Ferraro; Massimo Filippi; Nicola Fini; Gianluca Floris; Giuseppe Fuda; Salvatore Gallone; Giulia Gianferrari; Fabio Giannini; Maurizio Grassano; Lucia Greco; Barbara Iazzolino; Alessandro Introna; Vincenzo La Bella; Serena Lattante; Rocco Liguori; Giancarlo Logroscino; Francesco O. Logullo; Christian Lunetta; Paola Mandich; Jessica Mandrioli; Umberto Manera; Fiore Manganelli; Giuseppe Marangi; Kalliopi Marinou; Maria Giovanna Marrosu; Ilaria Martinelli; Sonia Messina; Cristina Moglia; Lorena Mosca; Maria R. Murru; Paola Origone; Carla Passaniti; Cristina Petrelli; Antonio Petrucci; Susanna Pozzi; Maura Pugliatti; Angelo Quattrini; Claudia Ricci; Giulia Riolo; Nilo Riva; Massimo Russo; Mario Sabatelli; Paolina Salamone; Marco Salivetto; Fabrizio Salvi; Marialuisa Santarelli; Luca Sbaiz; Riccardo Sideri; Isabella Simone; Cecilia Simonini; Rossella Spataro; Raffaella Tanel; Gioacchino Tedeschi; Anna Ticca; Antonella Torriello; Stefania Tranquilli; Lucio Tremolizzo; Francesca Trojsi; Rosario Vasta; Veria Vacchiano; Giuseppe Vita; Paolo Volanti; Marcella Zollino; Elisabetta Zucchi

doi:10.1001/jamaneurol.2021.2598

Association of Variants in the SPTLC1 Gene with Juvenile Amyotrophic Lateral Sclerosis

Janel O. Johnson, Ruth Chia, Danny E. Miller, Rachel Li, Ravindran Kumaran, Yevgeniya Abramzon, Nada Alahmady, Alan E. Renton, Simon D. Topp, J. Raphael Gibbs, Mark R. Cookson, Marya S. Sabir, Clifton L. Dalgard, Claire Troakes, Ashley R. Jones, Aleksey Shatunov, Alfredo Iacoangeli, Ahmad Al Khleifat, Nicola Ticozzi, Vincenzo SilaniCinzia Gellera, Ian P. Blair, Carol Dobson-Stone, John B. Kwok, Emily S. Bonkowski, Robin Palvadeau, Pentti J. Tienari, Karen E. Morrison, Pamela J. Shaw, Ammar Al-Chalabi, Robert H. Brown, Andrea Calvo, Gabriele Mora, Hind Al-Saif, Marc Gotkine, Fawn Leigh, Irene J. Chang, Seth J. Perlman, Ian Glass, Anna I. Scott, Christopher E. Shaw, A. Nazli Basak, John E. Landers, Adriano Chiò, Thomas O. Crawford, Bradley N. Smith, Bryan J. Traynor, Bradley N. Smith, Claudia Fallini, Athina Soragia Gkazi, Simon D. Topp, Emma L. Scotter, Kevin P. Kenna, Pamela Keagle, Cinzia Tiloca, Caroline Vance, Claire Troakes, Claudia Colombrita, Andrew King, Viviana Pensato, Barbara Castellotti, Frank Baas, Anneloor L.M.A. Ten Asbroek, Diane McKenna-Yasek, Russell L. McLaughlin, Meraida Polak, Seneshaw Asress, Jesús Esteban-Pérez, Zorica Stevic, Sandra D'Alfonso, Letizia Mazzini, Giacomo P. Comi, Roberto Del Bo, Mauro Ceroni, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Wouter Van Rheenen, Rosa Rademakers, Marka Van Blitterswijk, Giuseppe Lauria, Stefano Duga, Stefania Corti, Cristina Cereda, Lucia Corrado, Gianni Sorarù, Kelly L. Williams, Garth A. Nicholson, Ian P. Blair, Claire Leblond-Manry, Guy A. Rouleau, Orla Hardiman, Karen E. Morrison, Jan H. Veldink, Leonard H. Van Den Berg, Hardev Pall, Martin R. Turner, Kevin Talbot, Franco Taroni, Alberto García-Redondo, Zheyang Wu, Jonathan D. Glass, Cinzia Gellera, Antonia Ratti, Robert H. Brown, John E. Landers, Clifton L. Dalgard, Adelani Adeleye, Anthony R. Soltis, Camille Alba, Coralie Viollet, Dagmar Bacikova, Daniel N. Hupalo, Gauthaman Sukumar, Harvey B. Pollard, Matthew D. Wilkerson, Elisa Mc Grath Martinez, Yevgeniya Abramzon, Sarah Ahmed, Sampath Arepalli, Robert H. Baloh, Robert Bowser, Christopher B. Brady, Alexis Brice, James Broach, Roy H. Campbell, William Camu, John Cooper-Knock, Jinhui Ding, Carsten Drepper, Vivian E. Drory, Travis L. Dunckley, John D. Eicher, Bryce K. England, Faraz Faghri, Eva Feldman, Mary Kay Floeter, Pietro Fratta, Joshua T. Geiger, Glenn Gerhard, J. Raphael Gibbs, Summer B. Gibson, Jonathan D. Glass, John Hardy, Matthew B. Harms, Terry D. Heiman-Patterson, Dena G. Hernandez, Lilja Jansson, Janine Kirby, Neil W. Kowall, Hannu Laaksovirta, Natalie Landeck, Francesco Landi, Isabelle Le Ber, Serge Lumbroso, Daniel J.L. Macgowan, Nicholas J. Maragakis, Kevin Mouzat, Natalie A. Murphy, Liisa Myllykangas, Mike A. Nalls, Richard W. Orrell, Lyle W. Ostrow, Roger Pamphlett, Stuart Pickering-Brown, Erik P. Pioro, Olga Pletnikova, Hannah A. Pliner, Stefan M. Pulst, John M. Ravits, Alan E. Renton, Alberto Rivera, Wim Robberecht, Ekaterina Rogaeva, Sara Rollinson, Jeffrey D. Rothstein, Sonja W. Scholz, Michael Sendtner, Katie C. Sidle, Zachary Simmons, Andrew B. Singleton, Nathan Smith, David J. Stone, Pentti J. Tienari, Juan C. Troncoso, Miko Valori, Philip Van Damme, Vivianna M. Van Deerlin, Ludo Van Den Bosch, Lorne Zinman, John E. Landers, Adriano Chiò, Bryan J. Traynor, Stefania M. Angelocola, Francesco P. Ausiello, Marco Barberis, Ilaria Bartolomei, Stefania Battistini, Enrica Bersano, Giulia Bisogni, Giuseppe Borghero, Maura Brunetti, Corrado Cabona, Andrea Calvo, Fabrizio Canale, Antonio Canosa, Teresa A. Cantisani, Margherita Capasso, Claudia Caponnetto, Patrizio Cardinali, Paola Carrera, Federico Casale, Adriano Chiò, Tiziana Colletti, Francesca L. Conforti, Amelia Conte, Elisa Conti, Massimo Corbo, Stefania Cuccu, Eleonora Dalla Bella, Eustachio D'Errico, Giovanni Demarco, Raffaele Dubbioso, Carlo Ferrarese, Pilar M. Ferraro, Massimo Filippi, Nicola Fini, Gianluca Floris, Giuseppe Fuda, Salvatore Gallone, Giulia Gianferrari, Fabio Giannini, Maurizio Grassano, Lucia Greco, Barbara Iazzolino, Alessandro Introna, Vincenzo La Bella, Serena Lattante, Rocco Liguori, Giancarlo Logroscino, Francesco O. Logullo, Christian Lunetta, Paola Mandich, Jessica Mandrioli, Umberto Manera, Fiore Manganelli, Giuseppe Marangi, Kalliopi Marinou, Maria Giovanna Marrosu, Ilaria Martinelli, Sonia Messina, Cristina Moglia, Lorena Mosca, Maria R. Murru, Paola Origone, Carla Passaniti, Cristina Petrelli, Antonio Petrucci, Susanna Pozzi, Maura Pugliatti, Angelo Quattrini, Claudia Ricci, Giulia Riolo, Nilo Riva, Massimo Russo, Mario Sabatelli, Paolina Salamone, Marco Salivetto, Fabrizio Salvi, Marialuisa Santarelli, Luca Sbaiz, Riccardo Sideri, Isabella Simone, Cecilia Simonini, Rossella Spataro, Raffaella Tanel, Gioacchino Tedeschi, Anna Ticca, Antonella Torriello, Stefania Tranquilli, Lucio Tremolizzo, Francesca Trojsi, Rosario Vasta, Veria Vacchiano, Giuseppe Vita, Paolo Volanti, Marcella Zollino, Elisabetta Zucchi

Nash Family Department of Neuroscience

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1236-1248
Number of pages	13
Journal	JAMA Neurology
Volume	78
Issue number	10
DOIs	https://doi.org/10.1001/jamaneurol.2021.2598
State	Published - 1 Oct 2021

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10.1001/jamaneurol.2021.2598

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Johnson, J. O., Chia, R., Miller, D. E., Li, R., Kumaran, R., Abramzon, Y., Alahmady, N., Renton, A. E., Topp, S. D., Gibbs, J. R., Cookson, M. R., Sabir, M. S., Dalgard, C. L., Troakes, C., Jones, A. R., Shatunov, A., Iacoangeli, A., Al Khleifat, A., Ticozzi, N., ... Zucchi, E. (2021). Association of Variants in the SPTLC1 Gene with Juvenile Amyotrophic Lateral Sclerosis. JAMA Neurology, 78(10), 1236-1248. https://doi.org/10.1001/jamaneurol.2021.2598

@article{3c14239c59114fdcadd4e562bcf9b53f,

title = "Association of Variants in the SPTLC1 Gene with Juvenile Amyotrophic Lateral Sclerosis",

abstract = "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.",

author = "Johnson, {Janel O.} and Ruth Chia and Miller, {Danny E.} and Rachel Li and Ravindran Kumaran and Yevgeniya Abramzon and Nada Alahmady and Renton, {Alan E.} and Topp, {Simon D.} and Gibbs, {J. Raphael} and Cookson, {Mark R.} and Sabir, {Marya S.} and Dalgard, {Clifton L.} and Claire Troakes and Jones, {Ashley R.} and Aleksey Shatunov and Alfredo Iacoangeli and {Al Khleifat}, Ahmad and Nicola Ticozzi and Vincenzo Silani and Cinzia Gellera and Blair, {Ian P.} and Carol Dobson-Stone and Kwok, {John B.} and Bonkowski, {Emily S.} and Robin Palvadeau and Tienari, {Pentti J.} and Morrison, {Karen E.} and Shaw, {Pamela J.} and Ammar Al-Chalabi and Brown, {Robert H.} and Andrea Calvo and Gabriele Mora and Hind Al-Saif and Marc Gotkine and Fawn Leigh and Chang, {Irene J.} and Perlman, {Seth J.} and Ian Glass and Scott, {Anna I.} and Shaw, {Christopher E.} and Basak, {A. Nazli} and Landers, {John E.} and Adriano Chi{\`o} and Crawford, {Thomas O.} and Smith, {Bradley N.} and Traynor, {Bryan J.} and Smith, {Bradley N.} and Claudia Fallini and Gkazi, {Athina Soragia} and Topp, {Simon D.} and Scotter, {Emma L.} and Kenna, {Kevin P.} and Pamela Keagle and Cinzia Tiloca and Caroline Vance and Claire Troakes and Claudia Colombrita and Andrew King and Viviana Pensato and Barbara Castellotti and Frank Baas and {Ten Asbroek}, {Anneloor L.M.A.} and Diane McKenna-Yasek and McLaughlin, {Russell L.} and Meraida Polak and Seneshaw Asress and Jes{\'u}s Esteban-P{\'e}rez and Zorica Stevic and Sandra D'Alfonso and Letizia Mazzini and Comi, {Giacomo P.} and {Del Bo}, Roberto and Mauro Ceroni and Stella Gagliardi and Giorgia Querin and Cinzia Bertolin and {Van Rheenen}, Wouter and Rosa Rademakers and {Van Blitterswijk}, Marka and Giuseppe Lauria and Stefano Duga and Stefania Corti and Cristina Cereda and Lucia Corrado and Gianni Sorar{\`u} and Williams, {Kelly L.} and Nicholson, {Garth A.} and Blair, {Ian P.} and Claire Leblond-Manry and Rouleau, {Guy A.} and Orla Hardiman and Morrison, {Karen E.} and Veldink, {Jan H.} and {Van Den Berg}, {Leonard H.} and Hardev Pall and Turner, {Martin R.} and Kevin Talbot and Franco Taroni and Alberto Garc{\'i}a-Redondo and Zheyang Wu and Glass, {Jonathan D.} and Cinzia Gellera and Antonia Ratti and Brown, {Robert H.} and Landers, {John E.} and Dalgard, {Clifton L.} and Adelani Adeleye and Soltis, {Anthony R.} and Camille Alba and Coralie Viollet and Dagmar Bacikova and Hupalo, {Daniel N.} and Gauthaman Sukumar and Pollard, {Harvey B.} and Wilkerson, {Matthew D.} and Martinez, {Elisa Mc Grath} and Yevgeniya Abramzon and Sarah Ahmed and Sampath Arepalli and Baloh, {Robert H.} and Robert Bowser and Brady, {Christopher B.} and Alexis Brice and James Broach and Campbell, {Roy H.} and William Camu and John Cooper-Knock and Jinhui Ding and Carsten Drepper and Drory, {Vivian E.} and Dunckley, {Travis L.} and Eicher, {John D.} and England, {Bryce K.} and Faraz Faghri and Eva Feldman and Floeter, {Mary Kay} and Pietro Fratta and Geiger, {Joshua T.} and Glenn Gerhard and Gibbs, {J. Raphael} and Gibson, {Summer B.} and Glass, {Jonathan D.} and John Hardy and Harms, {Matthew B.} and Heiman-Patterson, {Terry D.} and Hernandez, {Dena G.} and Lilja Jansson and Janine Kirby and Kowall, {Neil W.} and Hannu Laaksovirta and Natalie Landeck and Francesco Landi and {Le Ber}, Isabelle and Serge Lumbroso and Macgowan, {Daniel J.L.} and Maragakis, {Nicholas J.} and Kevin Mouzat and Murphy, {Natalie A.} and Liisa Myllykangas and Nalls, {Mike A.} and Orrell, {Richard W.} and Ostrow, {Lyle W.} and Roger Pamphlett and Stuart Pickering-Brown and Pioro, {Erik P.} and Olga Pletnikova and Pliner, {Hannah A.} and Pulst, {Stefan M.} and Ravits, {John M.} and Renton, {Alan E.} and Alberto Rivera and Wim Robberecht and Ekaterina Rogaeva and Sara Rollinson and Rothstein, {Jeffrey D.} and Scholz, {Sonja W.} and Michael Sendtner and Sidle, {Katie C.} and Zachary Simmons and Singleton, {Andrew B.} and Nathan Smith and Stone, {David J.} and Tienari, {Pentti J.} and Troncoso, {Juan C.} and Miko Valori and {Van Damme}, Philip and {Van Deerlin}, {Vivianna M.} and {Van Den Bosch}, Ludo and Lorne Zinman and Landers, {John E.} and Adriano Chi{\`o} and Traynor, {Bryan J.} and Angelocola, {Stefania M.} and Ausiello, {Francesco P.} and Marco Barberis and Ilaria Bartolomei and Stefania Battistini and Enrica Bersano and Giulia Bisogni and Giuseppe Borghero and Maura Brunetti and Corrado Cabona and Andrea Calvo and Fabrizio Canale and Antonio Canosa and Cantisani, {Teresa A.} and Margherita Capasso and Claudia Caponnetto and Patrizio Cardinali and Paola Carrera and Federico Casale and Adriano Chi{\`o} and Tiziana Colletti and Conforti, {Francesca L.} and Amelia Conte and Elisa Conti and Massimo Corbo and Stefania Cuccu and {Dalla Bella}, Eleonora and Eustachio D'Errico and Giovanni Demarco and Raffaele Dubbioso and Carlo Ferrarese and Ferraro, {Pilar M.} and Massimo Filippi and Nicola Fini and Gianluca Floris and Giuseppe Fuda and Salvatore Gallone and Giulia Gianferrari and Fabio Giannini and Maurizio Grassano and Lucia Greco and Barbara Iazzolino and Alessandro Introna and {La Bella}, Vincenzo and Serena Lattante and Rocco Liguori and Giancarlo Logroscino and Logullo, {Francesco O.} and Christian Lunetta and Paola Mandich and Jessica Mandrioli and Umberto Manera and Fiore Manganelli and Giuseppe Marangi and Kalliopi Marinou and Marrosu, {Maria Giovanna} and Ilaria Martinelli and Sonia Messina and Cristina Moglia and Lorena Mosca and Murru, {Maria R.} and Paola Origone and Carla Passaniti and Cristina Petrelli and Antonio Petrucci and Susanna Pozzi and Maura Pugliatti and Angelo Quattrini and Claudia Ricci and Giulia Riolo and Nilo Riva and Massimo Russo and Mario Sabatelli and Paolina Salamone and Marco Salivetto and Fabrizio Salvi and Marialuisa Santarelli and Luca Sbaiz and Riccardo Sideri and Isabella Simone and Cecilia Simonini and Rossella Spataro and Raffaella Tanel and Gioacchino Tedeschi and Anna Ticca and Antonella Torriello and Stefania Tranquilli and Lucio Tremolizzo and Francesca Trojsi and Rosario Vasta and Veria Vacchiano and Giuseppe Vita and Paolo Volanti and Marcella Zollino and Elisabetta Zucchi",

year = "2021",

month = oct,

day = "1",

doi = "10.1001/jamaneurol.2021.2598",

language = "English",

volume = "78",

pages = "1236--1248",

journal = "JAMA Neurology",

issn = "2168-6149",

publisher = "American Medical Association",

number = "10",

}

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, 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, Smith, BN, 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, Pall, H, Turner, MR, Talbot, K, Taroni, F, García-Redondo, A, Wu, Z, Glass, JD, Gellera, C, Ratti, A, Brown, RH, Landers, JE, Dalgard, CL, Adeleye, A, Soltis, AR, Alba, C, Viollet, C, Bacikova, D, Hupalo, DN, Sukumar, G, Pollard, HB, Wilkerson, MD, Martinez, EMG, Abramzon, Y, Ahmed, S, Arepalli, S, Baloh, RH, Bowser, R, Brady, CB, Brice, A, Broach, J, Campbell, RH, Camu, W, 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, 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, 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, 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, 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 2021, 'Association of Variants in the SPTLC1 Gene with Juvenile Amyotrophic Lateral Sclerosis', JAMA Neurology, vol. 78, no. 10, pp. 1236-1248. https://doi.org/10.1001/jamaneurol.2021.2598

TY - JOUR

T1 - Association of Variants in the SPTLC1 Gene with Juvenile Amyotrophic Lateral Sclerosis

AU - Johnson, Janel O.

AU - Chia, Ruth

AU - Miller, Danny E.

AU - Li, Rachel

AU - Kumaran, Ravindran

AU - Abramzon, Yevgeniya

AU - Alahmady, Nada

AU - Renton, Alan E.

AU - Topp, Simon D.

AU - Gibbs, J. Raphael

AU - Cookson, Mark R.

AU - Sabir, Marya S.

AU - Dalgard, Clifton L.

AU - Troakes, Claire

AU - Jones, Ashley R.

AU - Shatunov, Aleksey

AU - Iacoangeli, Alfredo

AU - Al Khleifat, Ahmad

AU - Ticozzi, Nicola

AU - Silani, Vincenzo

AU - Gellera, Cinzia

AU - Blair, Ian P.

AU - Dobson-Stone, Carol

AU - Kwok, John B.

AU - Bonkowski, Emily S.

AU - Palvadeau, Robin

AU - Tienari, Pentti J.

AU - Morrison, Karen E.

AU - Shaw, Pamela J.

AU - Al-Chalabi, Ammar

AU - Brown, Robert H.

AU - Calvo, Andrea

AU - Mora, Gabriele

AU - Al-Saif, Hind

AU - Gotkine, Marc

AU - Leigh, Fawn

AU - Chang, Irene J.

AU - Perlman, Seth J.

AU - Glass, Ian

AU - Scott, Anna I.

AU - Shaw, Christopher E.

AU - Basak, A. Nazli

AU - Landers, John E.

AU - Chiò, Adriano

AU - Crawford, Thomas O.

AU - Smith, Bradley N.

AU - Traynor, Bryan J.

AU - Smith, Bradley N.

AU - Fallini, Claudia

AU - Gkazi, Athina Soragia

AU - Topp, Simon D.

AU - Scotter, Emma L.

AU - Kenna, Kevin P.

AU - Keagle, Pamela

AU - Tiloca, Cinzia

AU - Vance, Caroline

AU - Troakes, Claire

AU - Colombrita, Claudia

AU - King, Andrew

AU - Pensato, Viviana

AU - Castellotti, Barbara

AU - Baas, Frank

AU - Ten Asbroek, Anneloor L.M.A.

AU - McKenna-Yasek, Diane

AU - McLaughlin, Russell L.

AU - Polak, Meraida

AU - Asress, Seneshaw

AU - Esteban-Pérez, Jesús

AU - Stevic, Zorica

AU - D'Alfonso, Sandra

AU - Mazzini, Letizia

AU - Comi, Giacomo P.

AU - Del Bo, Roberto

AU - Ceroni, Mauro

AU - Gagliardi, Stella

AU - Querin, Giorgia

AU - Bertolin, Cinzia

AU - Van Rheenen, Wouter

AU - Rademakers, Rosa

AU - Van Blitterswijk, Marka

AU - Lauria, Giuseppe

AU - Duga, Stefano

AU - Corti, Stefania

AU - Cereda, Cristina

AU - Corrado, Lucia

AU - Sorarù, Gianni

AU - Williams, Kelly L.

AU - Nicholson, Garth A.

AU - Blair, Ian P.

AU - Leblond-Manry, Claire

AU - Rouleau, Guy A.

AU - Hardiman, Orla

AU - Morrison, Karen E.

AU - Veldink, Jan H.

AU - Van Den Berg, Leonard H.

AU - Pall, Hardev

AU - Turner, Martin R.

AU - Talbot, Kevin

AU - Taroni, Franco

AU - García-Redondo, Alberto

AU - Wu, Zheyang

AU - Glass, Jonathan D.

AU - Gellera, Cinzia

AU - Ratti, Antonia

AU - Brown, Robert H.

AU - Landers, John E.

AU - Dalgard, Clifton L.

AU - Adeleye, Adelani

AU - Soltis, Anthony R.

AU - Alba, Camille

AU - Viollet, Coralie

AU - Bacikova, Dagmar

AU - Hupalo, Daniel N.

AU - Sukumar, Gauthaman

AU - Pollard, Harvey B.

AU - Wilkerson, Matthew D.

AU - Martinez, Elisa Mc Grath

AU - Abramzon, Yevgeniya

AU - Ahmed, Sarah

AU - Arepalli, Sampath

AU - Baloh, Robert H.

AU - Bowser, Robert

AU - Brady, Christopher B.

AU - Brice, Alexis

AU - Broach, James

AU - Campbell, Roy H.

AU - Camu, William

AU - Cooper-Knock, John

AU - Ding, Jinhui

AU - Drepper, Carsten

AU - Drory, Vivian E.

AU - Dunckley, Travis L.

AU - Eicher, John D.

AU - England, Bryce K.

AU - Faghri, Faraz

AU - Feldman, Eva

AU - Floeter, Mary Kay

AU - Fratta, Pietro

AU - Geiger, Joshua T.

AU - Gerhard, Glenn

AU - Gibbs, J. Raphael

AU - Gibson, Summer B.

AU - Glass, Jonathan D.

AU - Hardy, John

AU - Harms, Matthew B.

AU - Heiman-Patterson, Terry D.

AU - Hernandez, Dena G.

AU - Jansson, Lilja

AU - Kirby, Janine

AU - Kowall, Neil W.

AU - Laaksovirta, Hannu

AU - Landeck, Natalie

AU - Landi, Francesco

AU - Le Ber, Isabelle

AU - Lumbroso, Serge

AU - Macgowan, Daniel J.L.

AU - Maragakis, Nicholas J.

AU - Mouzat, Kevin

AU - Murphy, Natalie A.

AU - Myllykangas, Liisa

AU - Nalls, Mike A.

AU - Orrell, Richard W.

AU - Ostrow, Lyle W.

AU - Pamphlett, Roger

AU - Pickering-Brown, Stuart

AU - Pioro, Erik P.

AU - Pletnikova, Olga

AU - Pliner, Hannah A.

AU - Pulst, Stefan M.

AU - Ravits, John M.

AU - Renton, Alan E.

AU - Rivera, Alberto

AU - Robberecht, Wim

AU - Rogaeva, Ekaterina

AU - Rollinson, Sara

AU - Rothstein, Jeffrey D.

AU - Scholz, Sonja W.

AU - Sendtner, Michael

AU - Sidle, Katie C.

AU - Simmons, Zachary

AU - Singleton, Andrew B.

AU - Smith, Nathan

AU - Stone, David J.

AU - Tienari, Pentti J.

AU - Troncoso, Juan C.

AU - Valori, Miko

AU - Van Damme, Philip

AU - Van Deerlin, Vivianna M.

AU - Van Den Bosch, Ludo

AU - Zinman, Lorne

AU - Landers, John E.

AU - Chiò, Adriano

AU - Traynor, Bryan J.

AU - Angelocola, Stefania M.

AU - Ausiello, Francesco P.

AU - Barberis, Marco

AU - Bartolomei, Ilaria

AU - Battistini, Stefania

AU - Bersano, Enrica

AU - Bisogni, Giulia

AU - Borghero, Giuseppe

AU - Brunetti, Maura

AU - Cabona, Corrado

AU - Calvo, Andrea

AU - Canale, Fabrizio

AU - Canosa, Antonio

AU - Cantisani, Teresa A.

AU - Capasso, Margherita

AU - Caponnetto, Claudia

AU - Cardinali, Patrizio

AU - Carrera, Paola

AU - Casale, Federico

AU - Chiò, Adriano

AU - Colletti, Tiziana

AU - Conforti, Francesca L.

AU - Conte, Amelia

AU - Conti, Elisa

AU - Corbo, Massimo

AU - Cuccu, Stefania

AU - Dalla Bella, Eleonora

AU - D'Errico, Eustachio

AU - Demarco, Giovanni

AU - Dubbioso, Raffaele

AU - Ferrarese, Carlo

AU - Ferraro, Pilar M.

AU - Filippi, Massimo

AU - Fini, Nicola

AU - Floris, Gianluca

AU - Fuda, Giuseppe

AU - Gallone, Salvatore

AU - Gianferrari, Giulia

AU - Giannini, Fabio

AU - Grassano, Maurizio

AU - Greco, Lucia

AU - Iazzolino, Barbara

AU - Introna, Alessandro

AU - La Bella, Vincenzo

AU - Lattante, Serena

AU - Liguori, Rocco

AU - Logroscino, Giancarlo

AU - Logullo, Francesco O.

AU - Lunetta, Christian

AU - Mandich, Paola

AU - Mandrioli, Jessica

AU - Manera, Umberto

AU - Manganelli, Fiore

AU - Marangi, Giuseppe

AU - Marinou, Kalliopi

AU - Marrosu, Maria Giovanna

AU - Martinelli, Ilaria

AU - Messina, Sonia

AU - Moglia, Cristina

AU - Mosca, Lorena

AU - Murru, Maria R.

AU - Origone, Paola

AU - Passaniti, Carla

AU - Petrelli, Cristina

AU - Petrucci, Antonio

AU - Pozzi, Susanna

AU - Pugliatti, Maura

AU - Quattrini, Angelo

AU - Ricci, Claudia

AU - Riolo, Giulia

AU - Riva, Nilo

AU - Russo, Massimo

AU - Sabatelli, Mario

AU - Salamone, Paolina

AU - Salivetto, Marco

AU - Salvi, Fabrizio

AU - Santarelli, Marialuisa

AU - Sbaiz, Luca

AU - Sideri, Riccardo

AU - Simone, Isabella

AU - Simonini, Cecilia

AU - Spataro, Rossella

AU - Tanel, Raffaella

AU - Tedeschi, Gioacchino

AU - Ticca, Anna

AU - Torriello, Antonella

AU - Tranquilli, Stefania

AU - Tremolizzo, Lucio

AU - Trojsi, Francesca

AU - Vasta, Rosario

AU - Vacchiano, Veria

AU - Vita, Giuseppe

AU - Volanti, Paolo

AU - Zollino, Marcella

AU - Zucchi, Elisabetta

PY - 2021/10/1

Y1 - 2021/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85114289450&partnerID=8YFLogxK

U2 - 10.1001/jamaneurol.2021.2598

DO - 10.1001/jamaneurol.2021.2598

M3 - Article

AN - SCOPUS:85114289450

SN - 2168-6149

VL - 78

SP - 1236

EP - 1248

JO - JAMA Neurology

JF - JAMA Neurology

IS - 10

ER -

Association of Variants in the SPTLC1 Gene with Juvenile Amyotrophic Lateral Sclerosis

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