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 | |
| Publication status | Published - Oct 2021 |
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In: JAMA Neurology, Vol. 78, No. 10, 10.2021, p. 1236-1248.
Research output: Contribution to journal › Article › peer-review
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 - Ticozzi, Nicola
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 - Al-Chalabi, Ammar
AU - Pall, Hardev
AU - Shaw, Pamela J.
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 - Silani, Vincenzo
AU - Shaw, Christopher E.
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 - Chia, Ruth
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 - Mora, Gabriele
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 - Lauria, Giuseppe
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 - Mora, Gabriele
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
N1 - Funding Information: Traynor hold the US, Canadian, and European patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion in C9orf72. Dr Chiò serves on scientific advisory boards for Biogen Idec, Cytokinetics, Italfarmaco, and Neuraltus. Dr Al-Chalabi reports consultancies for Biogen Idec, Cytokinetics Inc, OrionPharma, Chronos Therapeutics, and Mitsubishi-Tanabe Pharma. Dr Landers is a member of the scientific advisory board for Cerevel Therapeutics and a consultant and provides expert testimony for Perkins Coie. Dr Topp reports grants from UK Dementia Research Institute during the conduct of the study. Dr Dobson-Stone reports grants from National Health and Medical Research Council of Australia during the conduct of the study. Dr Kwok reports grants from National Health and Medical Research Council during the conduct of the study. Dr Tienari reports grants from Sigrid Juselius Foundation and Helsinki University Hospital during the conduct of the study. Dr Al-Chalabi reports grants from the UK Medical Research Council during the conduct of the study and has consulted for Biogen Idec, OrionPharma, Amylyx, BrainStorm, Mitsubishi Tanabe Pharma, Cytokinetics, and Apellis outside the submitted work. Dr Landers reports grants from the ALS Association and National Institute of Neurological Disorders and Stroke during the conduct of the study as well as personal fees from Cerevel Therapeutics and Perkins Coie outside the submitted work. Dr Chiò reports personal fees from Biogen Scientific and Cytokinetics Scientific outside the submitted work. Funding Information: Dr Traynor reports institutional support from Intramural Program of the National Institutes of Health; and grants from Packard Center, ALS Association, and Muscular Dystrophy Association during the conduct of the study; grants from Myasthenia Gravis foundation, Merck, US Centers for Disease Control and Prevention, US Veterans Administration, and Microsoft Research outside the submitted work; and is on the editorial board of JAMA Neurology; Journal of Neurology, Neurosurgery, and Psychiatry; Neurobiology of Aging; and Brain. Dr Stone is an employee of Cerevel Therapeutics. Dr Pollard reports grants from the National Institutes of Health during the conduct of the study. Dr Baloh is employed by Roche Pharmaceuticals. Dr Eicher is an employee of Merck and GlaxoSmithKline. Dr Faghri reports personal fees from National Institutes of Health outside the submitted work. Dr Feldman reports grants from the National Institutes of Health, US Centers for Disease Control and Prevention/ Agency for Toxic Substances and Disease Registry, Novo Nordisk Foundation, and JDRF and personal fees from Novartis outside the submitted work. Dr Geiger reports personal fees from the National Institutes of Health during the conduct of the study. Dr Harms reports grants from Biogen, ALS Association, and Project ALS during the conduct of the study as well as personal fees from Invitae and VariantBio outside the submitted work. Dr Heiman-Patterson reports grants from Mitsubishi Tanabe America and personal fees from Samus, Cytokinetics, ITF, and Orion outside the submitted work. Dr Le Ber reports grants from PHRC FTLD-exome and Investissements d’avenir during the conduct of the study as well as personal fees from Prevail Therapeutics and Alector outside the submitted work. Dr Maragakis reports grants from US Department of Defense and Answer ALS during the conduct of the study. Dr Murphy reports salary support from National Institute on Aging during the conduct of the study. Dr Nalls reports support from the National Institutes of Health. Dr Orrell reports grants from Motor Neurone Disease Association during the conduct of the study. Dr Ostrow reports grants from Target ALS Foundation during the conduct of the study and grants from ALS Association outside the submitted work. Dr Rothstein reports grants from Calico Therapeutics and GlaxoSmith Kline; personal fees from Expansion Therapeutics; and nonfinancial support from Ionis Pharmaceuticals outside the submitted work. Dr Scholz reports serving on editorial boards of the Journal of Parkinson’s Disease, Frontiers in Neurology, Frontiers in Neuroscience, Frontiers in Psychiatry, and JAMA Neurology. Dr Simmons reports personal fees from Biogen, Amylyx, and Alexion and grants from MT Pharma outside the submitted work. Dr Troncoso reports grants from the National Institutes of Health Alzheimer’s Disease Research Center during the conduct of the study. Dr Van Damme reports grants from CSL Behring and fees from Biogen, Alexion Pharmaceuticals, Ferrer, QurAlis, and Argenx paid to his institution outside the submitted work. Dr Baas reports personal fees from ComplementPharma outside the submitted work. Dr Hardiman reports grants from Science Foundation Ireland during the conduct of the study as well as personal fees from Taylor & Francis outside the submitted work. Dr Veldink reports grants from Biogen outside the submitted work. Dr van den Berg reports grants from Netherlands ALS Foundation during the conduct of the study. Dr Turner reports grants from Motor Neurone Disease Association as well as personal fees from Orphazyme, Oxford University Press, and BMA Journals outside the submitted work. Dr Taroni reports grants from Italian Ministry of Health during the conduct of the study as well as grants from Italian Ministry of Health and Fondazione Regionale per la Ricerca Biomedica (FRRB) outside the submitted work. Dr Corbo reports personal fees from Biogen outside the submitted work. Dr Filippi reports personal fees from Almiral, Alexion, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda, and Teva; grants from Biogen, Merck-Serono, Novartis, Roche, and Teva outside the submitted work; and is Editor-in-Chief of the Journal of Neurology and Associate Editor of Human Brain Mapping. Dr Liguori reports personal fees from ARGENX BV outside the submitted work. Dr Mandrioli reports nonfinancial support from Pfizer outside the submitted work. Dr Brice reports grants from Institut de France Prix de Recherche Allianz 2018, ANR–EPIC, France Parkinson + FRC, and APHP Extraction d’ADN à partir de prélèvements sanguins, conservation des échantillons d’ADN extraits et distributions d’aliquots d’ADN pour analyse outside the submitted work. Dr Bisogni reports personal fees from Alnylam outside the submitted work. Dr Tedeschi reports grants from Roche, Biogen, Allergan, Merck, Novartis, and Lilly outside the submitted work. Dr Bowser reports personal fees from Iron Horse Diagnostics outside the submitted work. No other disclosures were reported. Funding Information: part by the Intramural Research Programs of the National Institute on Aging (grant Z01-AG000949-02) and National Institute of Neurological Disorders and Stroke (grant ZIA-NS03154). The work was also funded by the Packard Center for ALS Research at Johns Hopkins, the ALS Association (grant 20-SI-508), the Muscular Dystrophy Association, the Italian Ministry of Health (grant RF-2016-02362405), the Italian Ministry of Education, University and Research (Progetti di Ricerca di Rilevante Interesse Nazionale [PRIN]; grant 2017SNW5MB), the Joint Programme–Neurodegenerative Disease Research (JPND; Brain-Mend projects) granted by Italian Ministry of Education, University and Research, and by the European Community’s Health Seventh Framework Programme (FP7/2007–2013; grant agreements 259867 and 278611), by the National Institute of Neurological Disorders and Stroke (grants R35 NS097261, R01NS073873, and R56NS073873), and by the Collaborative Health Initiative Research Program. This study was performed under the Department of Excellence grant of the Italian Ministry of Education, University and Research to the ‘Rita Levi Montalcini’ Department of Neuroscience, University of Torino, Italy. Additional funding was also provided by the Motor Neurone Disease Association (MNDA), the Medical Research Council, the Medical Research Foundation (MRF), the Van Geest Foundation, The Psychiatry Research Trust of the Institute of Psychiatry, Guy’s and St. Thomas’ Charity and the Noreen Murray Foundation, the Sigrid Juselius Foundation, the UK Dementia Research Institute, the National Health and Medical Research Council of Australia (grants 1095215 and 1092023), and through the following funding organization under Funding Information: the aegis of JPND: UK Medical Research Council (grants MR/L501529/1 and MR/R024804/1). This work was supported by the Canadian Consortium on Neurodegeneration in Aging, UK Dementia Research Institute, which is funded by the Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. Dr Al-Chalabi is supported by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre. Dr P. Shaw is supported as an NIHR Senior Investigator and by the Sheffield NIHR Biomedical Research Centre. Dr Dobson-Stone is supported by the Australian National Health and Medical Research Council (NHMRC) Boosting Dementia Research Leadership Fellowship 1138223 and by the University of Sydney. Dr Kwok is supported by NHMRC Dementia Research Team Grant 1095127. The Alzheimer’s Disease Sequencing Project (ADSP) is comprised of 2 Alzheimer’s Disease (AD) genetics consortia and 3 National Human Genome Research Institute (NHGRI)–funded Large-Scale Sequencing and Analysis Centers (LSAC). The 2 AD genetics consortia are the Alzheimer’s Disease Genetics Consortium (ADGC) funded by National Institute on Aging grant U01 AG032984, and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by National Institute on Aging grant R01 AG033193, the National Heart, Lung, and Blood Institute, other National Institutes of Health institutes, and other foreign governmental and nongovernmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 to Drs Schellenberg, Farrer, Pericak-Vance, Mayeux, and Haines; U01AG049505 to Dr Seshadri; U01AG049506 to Dr Boerwinkle; U01AG049507 to Dr Wijsman; and U01AG049508 to Dr Goate. The Discovery Extension Phase analysis is supported through U01AG052411 to Dr Goate, U01AG052410 to Dr Pericak-Vance, and U01 AG052409 to Drs Seshadri and Fornage. Data generation and harmonization in the Follow-up Phases is supported by U54AG052427 (to Drs Schellenberg and Wang). The ADGC cohorts include Adult Changes in Thought (ACT), the Alzheimer’s Disease Centers (ADC), the Chicago Health and Aging Project (CHAP), the Memory and Aging Project (MAP), Mayo Clinic, Mayo Parkinson’s Disease controls, University of Miami, the Multi-Institutional Research in Alzheimer’s Genetic Epidemiology Study (MIRAGE), the National Cell Repository for Alzheimer’s Disease (NCRAD), the National Institute on Aging Late Onset Alzheimer’s Disease Family Study (NIA-LOAD), the Religious Orders Study (ROS), the Texas Alzheimer’s Research and Care Consortium (TARC), Vanderbilt University/Case Western Reserve University (VAN/CWRU), the Washington Heights-Inwood Columbia Aging Project (WHICAP) and the Washington University Sequencing Project (WUSP), the Columbia University Hispanic–Estudio Familiar de Influencia Genetica de Alzheimer (EFIGA), the University of Toronto, and Genetic Differences (GD). The CHARGE cohorts are supported in part by National Heart, Lung, and Blood Institute infrastructure grant HL105756 (Psaty), RC2HL102419 (Boerwinkle), and the Neurology Working Group is supported by the National Institute on Aging R01 grant AG033193. The CHARGE cohorts participating in the ADSP include the following: Austrian Stroke Prevention Study (ASPS), ASPS-Family study, and the Prospective Dementia Registry-Austria (ASPS/PRODEM-Aus), the Atherosclerosis Risk in Communities (ARIC) Study, the Cardiovascular Health Study (CHS), the Erasmus Rucphen Family Study (ERF), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). ASPS is funded by the Austrian Science Fund (FWF) grants P20545-P05 and P13180 and the Medical University of Graz. The ASPS-Fam is funded by the Austrian Science Fund (FWF) project I904, the EU Joint Programme–Neurodegenerative Disease Research (JPND) in frame of the BRIDGET project (Austria, Ministry of Science) and the Medical University of Graz and the Steiermärkische Krankenanstalten Gesellschaft. PRODEM–Austria is supported by the Austrian Research Promotion agency (FFG) (project 827462) and by the Austrian National Bank (Anniversary Fund; project 15435). ARIC research is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Neurocognitive data in ARIC is collected by U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, and 2U01HL096917 from the National Institutes of Health, and with previous brain magnetic resonance imaging examinations funded by R01-HL70825 from the National Heart, Lung, and Blood Institute. CHS research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grants U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by R01AG023629, R01AG15928, and R01AG20098 from the National Institute on Aging. FHS research is supported by National Heart, Lung, and Blood Institute contracts N01-HC-25195 and HHSN268201500001I. This study was also supported by additional grants from the National Institute on Aging (R01s AG054076, AG049607, and AG033040) and National Institute of Neurological Disorders and Stroke (R01 NS017950). The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant 018947 (LSHG-CT-2006-01947) and also received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) and grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme “Quality of Life and Management of the Living Resources” of 5th Framework Programme (No. QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by a joint grant from the Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the municipality of Rotterdam. Genetic data sets are also supported by the Netherlands Organization of Scientific Research NWO Investments (175.010.2005.011; 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA; project 050-060-810). All studies are grateful to their participants, faculty, and staff. The content of these articles is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the US Department of Health and Human Services. The 4 Large-Scale Sequencing and Analysis Centers are the Human Genome Sequencing Center at the Baylor College of Medicine (U54 HG003273), the Broad Institute Genome Center (U54HG003067), The American Genome Center at the Uniformed Services University of the Health Sciences (U01AG057659), and the Washington University Genome Institute (U54HG003079). Biological samples, and associated phenotypic data used in primary data analyses were stored at study investigators’ institutions and at the National Cell Repository for Alzheimer’s Disease (NCRAD; U24AG021886) at Indiana University funded by National Institute on Aging. Associated phenotypic data used in primary and secondary data analyses were provided by study investigators, the National Institute on Aging–funded Alzheimer’s Disease Centers (ADCs), and the National Alzheimer’s Coordinating Center (NACC; U01AG016976) and the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS; U24AG041689) at the University of Pennsylvania, funded by the National Institute on Aging, and at the Database for Genotypes and Phenotypes (dbGaP; phs000572) funded by National Institutes of Health. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. Contributors to the Genetic Analysis Data included study investigators on projects that were individually funded by the National Institute on Aging and other National Institutes of Health institutes, and by private US organizations or foreign governmental or nongovernmental organizations. Drs Ticozzi, Silani, and Gellera were financially supported by the Italian Ministry of Health (grant RF-201302355764). Ms Palvadeau and Dr Basak’s research was funded by Suna and Inan Kirac Foundation, grant 2005-2023. The American Genome Center is supported by National Heart, Lung, and Blood Institute grant IAA-A-HL-007.001, the Defense Health Agency, and the Henry M. Jackson Foundation for the Advancement of Military Medicine. Funding Information: in our research. We also thank Kirsty McWalter, MS, and other staff of GeneDx, Gaithersburg, Maryland, for their assistance. This study used DNA samples, genotype data, and clinical data from the National Institute of Neurological Disorders and Stroke Repository at Coriell, the New York Brain Bank– The Taub Institute, Columbia University, Department of Veterans Affairs Biorepository Brain Bank (grant BX002466), the Baltimore Longitudinal Study of Aging, the Johns Hopkins University Alzheimer’s Disease Research Center (National Institutes of Health grant P50AG05146), the National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders at the University of Maryland, the MRC London Neurodegenerative Diseases Brain Bank, King’s College London, and the Alzheimer’s Disease Sequencing Project. Samples used in this research were obtained from the UK MND Collections funded by the MND Association and the Wellcome Trust. We thank the Suna and Inan Kirac Foundation for its dedicated mentorship and sustained support. We also thank the Koc University, Jan Veldink, MD (Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands), the Project MinE sequencing Consortium, Irmak Sahbaz, BSc, and Muge Kovancilar-Koc, MSc (Suna and Inan Kırac Foundation, Neurodegeneration Research Laboratory, KUTTAM, School of Medicine, Koc University, Istanbul, Turkey), the Neurodegeneration Research Laboratory staff, and the Laboratory of Neurogenetics (National Institutes of Health) staff for their collegial support and technical assistance. None of the contributors were compensated for their work. Publisher Copyright: © 2021 American Medical Association. All rights reserved.
PY - 2021/10
Y1 - 2021/10
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 -