Association of Variants in the <i>SPTLC1</i> Gene With Juvenile Amyotrophic Lateral Sclerosis
Janel O. Johnson(National Institutes of Health), Ruth Chia(National Institutes of Health), Danny E. Miller(Seattle Children's Hospital), Rachel Li(Children's Hospital of Richmond at VCU), Ravindran Kumaran(National Institutes of Health), Yevgeniya Abramzon(National Institutes of Health), Nada F. Alahmady(King's College London), Alan E. Renton(National Institutes of Health), Simon Topp(King's College London), J. Raphael Gibbs(National Institutes of Health), Mark Cookson(National Hospital for Neurology and Neurosurgery), Marya S. Sabir(National Institutes of Health), Clifton L. Dalgard(Uniformed Services University of the Health Sciences), Claire Troakes(King's College London), Ashley R. Jones(King's College London), Aleksey Shatunov(King's College London), Alfredo Iacoangeli(King's College London), Ahmad Al Khleifat(King's College London), Nicola Ticozzi(University of Milan), Vincenzo Silani(University of Milan), Cinzia Gellera(Fondazione IRCCS Istituto Neurologico Carlo Besta), Ian P. Blair(Macquarie University), Carol Dobson‐Stone(The University of Sydney), John B. Kwok(The University of Sydney), Emily Bonkowski(Seattle Children's Hospital), Robin Palvadeau(Koç University), Pentti J. Tienari(University of Helsinki), Karen Morrison(Queen's University Belfast), Pamela J. Shaw(University of Sheffield), Ammar Al‐Chalabi(King's College London), Robert H. Brown(University of Massachusetts Chan Medical School), Andrea Calvo(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Gabriele Mora(Istituti Clinici Scientifici Maugeri), Hind Al-Saif(Children's Hospital of Richmond at VCU), Marc Gotkine(Hebrew University of Jerusalem), Fawn Leigh(Seattle Children's Hospital), Irene J. Chang(University of Washington Medical Center), Seth J. Perlman(Seattle Children's Hospital), Ian A. Glass(Seattle Children's Hospital), Anna I. Scott(Seattle Children's Hospital), Christopher E. Shaw(King's College London), A. Nazlı Başak(Koç University), John E. Landers(University of Massachusetts Chan Medical School), Adriano Chiò(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Thomas O. Crawford(Johns Hopkins University), Bradley Smith(King's College London), Bryan J. Traynor(National Institutes of Health), Bradley Smith(King's College London), Nicola Ticozzi(University of Milan), Claudia Fallini(University of Massachusetts Chan Medical School), Athina Soragia Gkazi(King's College London), Simon Topp(King's College London), Emma L. Scotter(University of Auckland), Kevin P. Kenna(University of Massachusetts Chan Medical School), Pamela Keagle(University of Massachusetts Chan Medical School), Cinzia Tiloca(IRCCS Istituto Auxologico Italiano), Caroline Vance(King's College London), Claire Troakes(King's College London), Claudia Colombrita(IRCCS Istituto Auxologico Italiano), Andrew King(King's College London), Viviana Pensato(Fondazione IRCCS Istituto Neurologico Carlo Besta), Barbara Castellotti(Fondazione IRCCS Istituto Neurologico Carlo Besta), Frank Baas(Leiden University Medical Center), Anneloor L.M.A. ten Asbroek(Amsterdam UMC Location University of Amsterdam), Diane McKenna‐Yasek(University of Massachusetts Chan Medical School), Russell L. McLaughlin(Trinity College Dublin), Meraida Polak(Emory University), Seneshaw Asress(Emory University), Jesús Esteban‐Pérez(Research Institute Hospital 12 de Octubre), Zorica Stević(University of Belgrade), Sandra D’Alfonso(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Letizia Mazzini(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Giacomo P. Comi(Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico), Roberto Del Bo(Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico), Mauro Ceroni(University of Pavia), Stella Gagliardi(Center for Genomic Science), Giorgia Querin(University of Padua), Cinzia Bertolin(University of Padua), Wouter van Rheenen(University Medical Center Utrecht), Rosa Rademakers(Jacksonville College), Marka van Blitterswijk(Jacksonville College), Giuseppe Lauria(University of Milan), Stefano Duga(Humanitas University), Stefania Corti(Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico), Cristina Cereda(Center for Genomic Science), Lucia Corrado(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Gianni Sorarú(University of Padua), Kelly L. Williams(Macquarie University), Garth A. Nicholson(Concord Repatriation General Hospital), Ian P. Blair(Macquarie University), Claire Leblond-Manry(Institut Pasteur), Guy A. Rouleau(Montreal Neurological Institute and Hospital), Orla Hardiman(Trinity College Dublin), Karen Morrison(Queen's University Belfast), Jan H. Veldink(University Medical Center Utrecht), Leonard H. van den Berg(University Medical Center Utrecht), Ammar Al‐Chalabi(King's College London), Hardev Pall(University of Birmingham), Pamela J. Shaw(University of Sheffield), Martin R. Turner(University of Oxford), Kevin Talbot(University of Oxford), Franco Taroni(Fondazione IRCCS Istituto Neurologico Carlo Besta), Alberto García‐Redondo(Research Institute Hospital 12 de Octubre), Zheyang Wu(Worcester Polytechnic Institute), Jonathan D. Glass(Emory University), Cinzia Gellera(Fondazione IRCCS Istituto Neurologico Carlo Besta), Antonia Ratti(IRCCS Istituto Auxologico Italiano), Robert H. Brown(University of Massachusetts Chan Medical School), Vincenzo Silani(University of Milan), Christopher E. Shaw(King's College London), John E. Landers(University of Massachusetts Chan Medical School), Clifton L. Dalgard(Uniformed Services University of the Health Sciences), Adelani Adeleye(Henry M. Jackson Foundation), Anthony R. Soltis(Henry M. Jackson Foundation), Camille Alba(Henry M. Jackson Foundation), Coralie Viollet(Henry M. Jackson Foundation), Dagmar Bačíková(Henry M. Jackson Foundation), Daniel N. Hupalo(Henry M. Jackson Foundation), Gauthaman Sukumar(Henry M. Jackson Foundation), Harvey B. Pollard(Uniformed Services University of the Health Sciences), Matthew D. Wilkerson(Henry M. Jackson Foundation), Elisa McGrath Martinez(Henry M. Jackson Foundation), Yevgeniya Abramzon(National Institutes of Health), Sarah Ahmed(National Institute of Neurological Disorders and Stroke), Sampath Arepalli(National Institute on Aging), Robert H. Baloh(Cedars-Sinai Medical Center), Robert Bowser(Barrow Neurological Institute), Christopher B. Brady(VA Boston Healthcare System), Alexis Brice(Inserm), James R. Broach(Penn State Milton S. Hershey Medical Center), Roy H. Campbell(University of Illinois Urbana-Champaign), William Camu(Université de Montpellier), Ruth Chia(National Institutes of Health), Johnathan Cooper‐Knock(University of Sheffield), Jinhui Ding(National Institute on Aging), Carsten Drepper(University of Würzburg), Vivian E. Drory(Tel Aviv Sourasky Medical Center), Travis Dunckley(Arizona State University), John D. Eicher(United States Military Academy), Bryce England(National Institute of Mental Health), Faraz Faghri(University of Illinois Urbana-Champaign), Eva Feldman(University of Michigan), Mary Kay Floeter(National Institute of Neurological Disorders and Stroke), Pietro Fratta(Sobell House), Joshua T. Geiger(National Institute of Neurological Disorders and Stroke), Glenn S. Gerhard(Penn State Milton S. Hershey Medical Center), J. Raphael Gibbs(National Institutes of Health), Summer Gibson(University of Utah), Jonathan D. Glass(Emory University), John Hardy(University College London), Matthew Harms(Columbia University), Terry Heiman‐Patterson(Drexel University), Dena G. Hernandez(National Institute on Aging), Lilja Jansson(University of Helsinki), Janine Kirby(University of Sheffield), Neil W. Kowall(VA Boston Healthcare System), Hannu Laaksovirta(University of Helsinki), Natalie Landeck(National Institute on Aging), Francesco Landi(Università Cattolica del Sacro Cuore), Isabelle Le Ber(Inserm), Serge Lumbroso(Inserm), Daniel J. MacGowan(Mount Sinai Beth Israel), Nicholas J. Maragakis(Johns Hopkins University), Gabriele Mora(Istituti Clinici Scientifici Maugeri), Kévin Mouzat(Inserm), Natalie A. Murphy(National Institute on Aging), Liisa Myllykangas(University of Helsinki), Mike A. Nalls(National Institute on Aging), Richard W. Orrell(University College London), Lyle W. Ostrow(Johns Hopkins University), Roger Pamphlett(The University of Sydney), Stuart Pickering‐Brown(University of Manchester), Erik P. Pioro(Cleveland Clinic), Olga Pletniková(Johns Hopkins University), Hannah A. Pliner(National Institute on Aging), Stefan M. Pulst(University of Utah), John Ravits(University of California San Diego), Alan E. Renton(National Institutes of Health), Alberto Rivera(National Institute on Aging), Wim Robberecht(VIB-KU Leuven Center for Brain & Disease Research), Ekaterina Rogaeva(University of Toronto), Sara Rollinson(University of Manchester), Jeffrey D. Rothstein(Johns Hopkins University), Sonja W. Scholz(Johns Hopkins University), Michael Sendtner(University of Würzburg), Pamela J. Shaw(University of Sheffield), Katie Sidle(University College London), Zachary Simmons(Penn State Milton S. Hershey Medical Center), Andrew Singleton(National Institute on Aging), Nathan Smith(National Institute on Aging), David J. Stone(United States Military Academy), Pentti J. Tienari(University of Helsinki), Juan C. Troncoso(Johns Hopkins University), Miko Valori(University of Helsinki), Philip Van Damme(VIB-KU Leuven Center for Brain & Disease Research), Vivianna M Van Deerlin(University of Pennsylvania), Ludo Van Den Bosch(VIB-KU Leuven Center for Brain & Disease Research), Lorne Zinman(Sunnybrook Health Science Centre), John E. Landers(University of Massachusetts Chan Medical School), Adriano Chiò(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Bryan J. Traynor(National Institutes of Health), Stefania Angelocola, Francesco P. Ausiello(Neuroscience Institute), Marco Barberis(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Ilaria Bartolomei(Institute of Neurological Sciences), Stefania Battistini(University of Siena), Enrica Bersano(Fondazione IRCCS Istituto Neurologico Carlo Besta), Giulia Bisogni(Centro Clinico Nemo), Giuseppe Borghero(University of Cagliari), Maura Brunetti(University of Turin), Corrado Cabona(Ospedale Policlinico San Martino), Andrea Calvo(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Fabrizio Canale(University of Campania "Luigi Vanvitelli"), Antonio Canosa(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Teresa A. Cantisani(Azienda Ospedaliera di Perugia), Margherita Capasso(Ospedale SS. Annunziata), Claudia Caponnetto(Ospedale Policlinico San Martino), Patrizio Cardinali, Paola Carrera(Vita-Salute San Raffaele University), Federico Casale(University of Turin), Adriano Chiò(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Tiziana Colletti(University of Palermo), F. L. Conforti(University of Calabria), Amelia Conte(Centro Clinico Nemo), Elisa Conti(Azienda Ospedaliera San Gerardo), Massimo Corbo, Stefania Cuccu(University of Cagliari), Eleonora Dalla Bella(Fondazione IRCCS Istituto Neurologico Carlo Besta), Eustachio D’Errico(University of Bari Aldo Moro), Giovanni De Marco(University of Turin), Raffaele Dubbioso(University of Naples Federico II), Carlo Ferrarese(Azienda Ospedaliera San Gerardo), Pilar M. Ferraro(Ospedale Policlinico San Martino), Massimo Filippi(Vita-Salute San Raffaele University), Nicola Fini(Azienda Unita' Sanitaria Locale Di Modena), Gianluca Floris(University of Cagliari), Giuseppe Fuda(University of Turin), Salvatore Gallone(University of Turin), Giulia Gianferrari(Azienda Unita' Sanitaria Locale Di Modena), Fabio Giannini(University of Siena), Maurizio Grassano(University of Turin), Lucia Catherine Greco(Centro Clinico Nemo), Barbara Iazzolino(University of Turin), Alessandro Introna(University of Bari Aldo Moro), Vincenzo La Bella(University of Palermo), Serena Lattante(Università Cattolica del Sacro Cuore), Giuseppe Lauria(University of Milan), Rocco Liguori(University of Bologna), Giancarlo Logroscino(University of Bari Aldo Moro), Francesco Logullo(University of Macerata), Christian Lunetta(Centro Clinico Nemo), Paola Mandich(Ospedale Policlinico San Martino), Jessica Mandrioli(Azienda Unita' Sanitaria Locale Di Modena), Umberto Manera(University of Turin), Fiore Manganelli(University of Naples Federico II), Giuseppe Marangi(Università Cattolica del Sacro Cuore), Kalliopi Marinou(Istituti Clinici Scientifici Maugeri), Maria Giovanna Marrosu(University of Cagliari), Ilaria Martinelli(Azienda Unita' Sanitaria Locale Di Modena), Sonia Messina(University of Messina), Cristina Moglia(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Gabriele Mora(Istituti Clinici Scientifici Maugeri), Lorena Mosca(Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda), Maria Rita Murru(University of Cagliari), Paola Origone(Ospedale Policlinico San Martino), Carla Passaniti(University of Campania "Luigi Vanvitelli"), Cristina Petrelli(University of Macerata), Antonio Petrucci(IRCCS San Camillo Hospital), Susanna Pozzi(Centro Clinico Nemo), Maura Pugliatti(University of Ferrara), Angelo Quattrini(Vita-Salute San Raffaele University), Claudia Ricci(University of Siena), Giulia Riolo(University of Siena), Nilo Riva(Vita-Salute San Raffaele University), Massimo Russo(University of Messina), Mario Sabatelli(Università Cattolica del Sacro Cuore), Paolina Salamone(University of Turin), Marco Salivetto(Centro Clinico Nemo), Fabrizio Salvi(Institute of Neurological Sciences), Marialuisa Santarelli(Ospedale San Filippo Neri), Luca Sbaiz(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Riccardo Sideri(Istituti Clinici Scientifici Maugeri), Isabella Laura Simone(University of Bari Aldo Moro), Cecilia Simonini(Azienda Unita' Sanitaria Locale Di Modena), Rossella Spataro(University of Palermo), Raffaella Tanel(Ospedale Santa Chiara), Gioacchino Tedeschi(University of Campania "Luigi Vanvitelli"), Anna Ticca(Azienda Ospedaliera S.Maria), Antonella Torriello(Ospedali Riuniti San Giovanni di Dio e Ruggi d'Aragona), Stefania Tranquilli(University of Cagliari), Lucio Tremolizzo(Azienda Ospedaliera San Gerardo), Francesca Trojsi(University of Campania "Luigi Vanvitelli"), Rosario Vasta(University of Turin), Veria Vacchiano(Institute of Neurological Sciences), Giuseppe Vita(University of Messina), Paolo Volanti(Istituti Clinici Scientifici Maugeri), Marcella Zollino(Università Cattolica del Sacro Cuore), Elisabetta Zucchi(Azienda Unita' Sanitaria Locale Di Modena)
Cited by 82Open Access
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.
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