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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Pages (from-to)1236-1248
Number of pages13
JournalJAMA Neurology
Volume78
Issue number10
DOIs
StatePublished - 1 Oct 2021
Externally publishedYes

Funding

FundersFunder number
National Health and Medical Research Council
Mitsubishi Tanabe Pharma Corporation
National Health and Medical Research Council
Cytokinetics
Medical Research Council
ALS Association
National Institute of Neurological Disorders and Stroke
Novartis
Agence Nationale de la Recherche
Centers for Disease Control and Prevention
Alexion Pharmaceuticals
U.S. Department of Veterans Affairs
Juvenile Diabetes Research Foundation United States of America
Ferrer
National Institutes of Health
National Institutes of Health Alzheimer’s Disease Research Center
Motor Neurone Disease Association
Microsoft Research
Roche
Institut de France Prix de Recherche Allianz
Biogen
Science Foundation Ireland
Myasthenia Gravis foundation
EPIC, France Parkinson + FRC
Muscular Dystrophy Association
Alexion Pharmaceuticals
Packard Center
Merck
ALS Association
Novo Nordisk Fonden
Allergan
Myelin Repair Foundation
Seventh Framework Programme278611, 259867, R01NS073873, R56NS073873, R35 NS097261
Seventh Framework Programme
National Institute on AgingZ01-AG000949-02
National Institute on Aging
National Health and Medical Research Council1095215, 1092023
National Health and Medical Research Council
European Community’s Health Seventh Framework Programme
Motor Neurone Disease Association
Epidermolysis Bullosa Medical Research Foundation
Van Geest Foundation
ALS Association20-SI-508
ALS Association
Sigrid Juséliuksen Säätiö
EU Joint Programme – Neurodegenerative Disease Research
Ministero dell’Istruzione, dell’Università e della Ricerca2017SNW5MB
Ministero dell’Istruzione, dell’Università e della Ricerca
UK Dementia Research Institute
Motor Neurone Disease Association
Neurodegenerative Disease Research
Noreen Murray Foundation
Muscular Dystrophy Association
Medical Research Council
Guy's and St Thomas' Charity
Ministero della SaluteRF-2016-02362405
Ministero della Salute
National Institute of Neurological Disorders and StrokeZIA-NS03154
National Institute of Neurological Disorders and Stroke
Oesterreichische Nationalbank2U01HL096899, U01 2U01HL096812, 2U01HL096902, 2U01HL096814, 2U01HL096917, HHSN268201100006C, HHSN268201100005C, HHSN268201100008C, HHSN268201100007C, HHSN268201100009C, 15435, HHSN268201100011C, HHSN268201100010C, HHSN268201100012C
Oesterreichische Nationalbank
NIAGADSU24AG041689
University of Sydney1095127
University of Sydney
Austrian Science Fund
Russian Foundation for Basic Research
National Institute for Health Research
Ministerie van Onderwijs, Cultuur en Wetenschap
RIDE
U.S. National Library of Medicine
EU Joint Programme – Neurodegenerative Disease Research
Erasmus Medisch Centrum014-93-015
Erasmus Medisch Centrum
Erasmus Medisch Centrum
Department of Internal Medicine, University of Utah
Neurodegenerative Disease Research
Ministero della SaluteRF-201302355764
Ministero della Salute
Austrian Science FundP20545-P05, P13180
Austrian Science Fund
Seventh Framework ProgrammeHEALTH-F4-2007-201413
Seventh Framework Programme
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Steiermärkische Krankenanstalten Gesellschaft
Alzheimer's Society
National Heart, Lung, and Blood Institute
Cohorts for Heart and Aging Research in GenomicR01 AG033193
Ministerie van Volksgezondheid, Welzijn en Sport
Manchester Biomedical Research Centre
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site
Netherlands Organization for Health Research and Development
Erasmus Universiteit Rotterdam
National Institutes of HealthN01HC85081, U01HL080295, N01HC85082, N01HC85080, HHSN268201200036C, N01HC85086, N01HC85083, R01-HL70825, N01HC85079, HHSN268200800007C, U01HL130114, N01HC55222
National Institutes of Health
European Commission
Northern Gulf Institute
NWO-RFBR047.017.043
Quality of Life and Management of the Living Resources” of 5th Framework ProgrammeQLG2-CT-2002-01254
National Association for Colitis and Crohn's DiseaseU01AG016976
National Association for Colitis and Crohn's Disease
National Institutes of Health institutesRC2HL102419, AG033193, HL105756
Sixth Framework Programme018947, LSHG-CT-2006-01947
Sixth Framework Programme
Henry M. Jackson Foundation
Indiana University
Netherlands Genomics Initiative
National Institute on AgingU01 AG032984
National Institute on Aging
Österreichische Forschungsförderungsgesellschaft
Ministry of Science
Consortium canadien en neurodégénérescence associée au vieillissement
NCHAU24AG021886, 050-060-810
National Health and Medical Research Council
Maudsley Biomedical Research Centre
National Health and Medical Research Council1138223
National Health and Medical Research Council
Suna and Inan Kirac FoundationIAA-A-HL-007.001, 2005-2023
UK Dementia Research Institute
European Commission
Defense Health Agency
Netherlands Organization of Scientific Research NWO175.010.2005.011, 911-03-012
Medical Research Council
Alzheimer’s Disease Genetics Consortium
EUROSPAN
University of Pennsylvaniaphs000572
University of Pennsylvania
Alzheimer’s Research UK
Netherlands Consortium for Healthy Aging
Research Institute for Diseases in the Elderly
RIDE2
Medizinische Universität GrazI904
Medizinische Universität Graz
National Alzheimer’s Coordinating Center
ADGC
Österreichische Forschungsförderungsgesellschaft827462
Österreichische Forschungsförderungsgesellschaft
National Institute on Handicapped Research
ZonMw
Seventh Framework Programme
National Institute of Neurological Disorders and StrokeR01AG20098, R01AG023629, AG033040, N01-HC-25195, AG049607, R01 NS017950, HHSN268201500001I, R01s AG054076, R01AG15928
National Institute of Neurological Disorders and Stroke
Johns Hopkins University Alzheimer’s Disease Research Center
Wellcome Trust
National Institutes of HealthP50AG05146
National Institutes of Health
Taub Institute
National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders
Baltimore Longitudinal Study of Aging
New York Brain Bank
University of Maryland
National Institute of Neurological Disorders and Stroke Repository at Coriell
MRC London Neurodegenerative Diseases Brain Bank
Columbia University
MND Association
Department of Veterans Affairs Biorepository Brain BankBX002466
King’s College London

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