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. 2021 Oct 1;78(10):1236-1248.
doi: 10.1001/jamaneurol.2021.2598.

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

Janel O Johnson  1 , Ruth Chia  1 , Danny E Miller  2   3 , Rachel Li  4 , Ravindran Kumaran  5 , Yevgeniya Abramzon  1   6 , Nada Alahmady  7   8 , Alan E Renton  1   9   10   11 , Simon D Topp  7   12 , J Raphael Gibbs  13 , Mark R Cookson  6 , Marya S Sabir  14 , Clifton L Dalgard  15   16 , Claire Troakes  7 , Ashley R Jones  7 , Aleksey Shatunov  7 , Alfredo Iacoangeli  7 , Ahmad Al Khleifat  7 , Nicola Ticozzi  17   18 , Vincenzo Silani  17   18 , Cinzia Gellera  19 , Ian P Blair  20 , Carol Dobson-Stone  21   22 , John B Kwok  21   22 , Emily S Bonkowski  3 , Robin Palvadeau  23 , Pentti J Tienari  24 , Karen E Morrison  25 , Pamela J Shaw  26 , Ammar Al-Chalabi  7   27 , Robert H Brown Jr  28 , Andrea Calvo  29 , Gabriele Mora  30 , Hind Al-Saif  31 , Marc Gotkine  32 , Fawn Leigh  33 , Irene J Chang  2 , Seth J Perlman  33 , Ian Glass  2   3 , Anna I Scott  34   35 , Christopher E Shaw  7   12 , A Nazli Basak  23 , John E Landers  28 , Adriano Chiò  29   36 , Thomas O Crawford  37   38 , Bradley N Smith  7 , Bryan J Traynor  1   6   37   39 ; FALS Sequencing Consortium; American Genome Center; International ALS Genomics Consortium; and ITALSGEN Consortium; Bradley N Smith  40 , Nicola Ticozzi  41   18 , Claudia Fallini  28 , Athina Soragia Gkazi  40 , Simon D Topp  40   12 , Emma L Scotter  42 , Kevin P Kenna  28 , Pamela Keagle  28 , Cinzia Tiloca  43 , Caroline Vance  44 , Claire Troakes  44 , Claudia Colombrita  43 , Andrew King  40 , Viviana Pensato  45 , Barbara Castellotti  45 , Frank Baas  46 , Anneloor L M A Ten Asbroek  47 , Diane McKenna-Yasek  28 , Russell L McLaughlin  48 , Meraida Polak  49 , Seneshaw Asress  49 , Jesús Esteban-Pérez  50 , Zorica Stevic  51 , Sandra D'Alfonso  52 , Letizia Mazzini  53 , Giacomo P Comi  54 , Roberto Del Bo  54 , Mauro Ceroni  55   56 , Stella Gagliardi  57 , Giorgia Querin  58 , Cinzia Bertolin  58 , Wouter van Rheenen  59 , Rosa Rademakers  60 , Marka van Blitterswijk  60 , Giuseppe Lauria  61 , Stefano Duga  62   63 , Stefania Corti  54 , Cristina Cereda  57 , Lucia Corrado  52 , Gianni Sorarù  58 , Kelly L Williams  20 , Garth A Nicholson  20   64 , Ian P Blair  20 , Claire Leblond-Manry  65 , Guy A Rouleau  66 , Orla Hardiman  67 , Karen E Morrison  25 , Jan H Veldink  59 , Leonard H van den Berg  59 , Ammar Al-Chalabi  44 , Hardev Pall  68 , Pamela J Shaw  26 , Martin R Turner  69 , Kevin Talbot  69 , Franco Taroni  45 , Alberto García-Redondo  50 , Zheyang Wu  70 , Jonathan D Glass  49 , Cinzia Gellera  45 , Antonia Ratti  41 , Robert H Brown Jr  28 , Vincenzo Silani  41   18 , Christopher E Shaw  12   44 , John E Landers  28 , Clifton L Dalgard  16   15 , Adelani Adeleye  16   71 , Anthony R Soltis  16   71 , Camille Alba  16   71 , Coralie Viollet  16   71 , Dagmar Bacikova  16   71 , Daniel N Hupalo  16   71 , Gauthaman Sukumar  16   71 , Harvey B Pollard  16   15 , Matthew D Wilkerson  16   15   71 , Elisa McGrath Martinez  16   71 , Yevgeniya Abramzon  72   73 , Sarah Ahmed  74 , Sampath Arepalli  75 , Robert H Baloh  76 , Robert Bowser  77 , Christopher B Brady  78 , Alexis Brice  79   80 , James Broach  81 , Roy H Campbell  82 , William Camu  83 , Ruth Chia  72 , John Cooper-Knock  84 , Jinhui Ding  85 , Carsten Drepper  86 , Vivian E Drory  87 , Travis L Dunckley  88 , John D Eicher  89 , Bryce K England  90 , Faraz Faghri  82   91 , Eva Feldman  92 , Mary Kay Floeter  93 , Pietro Fratta  73 , Joshua T Geiger  74 , Glenn Gerhard  94 , J Raphael Gibbs  85 , Summer B Gibson  95 , Jonathan D Glass  96 , John Hardy  97 , Matthew B Harms  98 , Terry D Heiman-Patterson  99   100 , Dena G Hernandez  75 , Lilja Jansson  101 , Janine Kirby  84 , Neil W Kowall  102 , Hannu Laaksovirta  101 , Natalie Landeck  103 , Francesco Landi  104 , Isabelle Le Ber  79   80 , Serge Lumbroso  105 , Daniel J L MacGowan  106 , Nicholas J Maragakis  37 , Gabriele Mora  30 , Kevin Mouzat  105 , Natalie A Murphy  72 , Liisa Myllykangas  107 , Mike A Nalls  91   108 , Richard W Orrell  109 , Lyle W Ostrow  37 , Roger Pamphlett  110 , Stuart Pickering-Brown  111 , Erik P Pioro  112 , Olga Pletnikova  113 , Hannah A Pliner  72 , Stefan M Pulst  95 , John M Ravits  114 , Alan E Renton  72   115 , Alberto Rivera  72 , Wim Robberecht  116 , Ekaterina Rogaeva  117 , Sara Rollinson  111 , Jeffrey D Rothstein  37 , Sonja W Scholz  74   37 , Michael Sendtner  118 , Pamela J Shaw  84 , Katie C Sidle  97 , Zachary Simmons  119 , Andrew B Singleton  91 , Nathan Smith  103 , David J Stone  89 , Pentti J Tienari  101 , Juan C Troncoso  113 , Miko Valori  101 , Philip Van Damme  116   120 , Vivianna M Van Deerlin  121 , Ludo Van Den Bosch  116 , Lorne Zinman  122 , John E Landers  28 , Adriano Chiò  123   124 , Bryan J Traynor  72   97   37   39 , Stefania M Angelocola  125 , Francesco P Ausiello  124 , Marco Barberis  126 , Ilaria Bartolomei  127 , Stefania Battistini  128 , Enrica Bersano  129 , Giulia Bisogni  130 , Giuseppe Borghero  131 , Maura Brunetti  123 , Corrado Cabona  132 , Andrea Calvo  123   133 , Fabrizio Canale  134 , Antonio Canosa  123   133 , Teresa A Cantisani  135 , Margherita Capasso  136 , Claudia Caponnetto  132 , Patrizio Cardinali  125 , Paola Carrera  137 , Federico Casale  123 , Adriano Chiò  123   133 , Tiziana Colletti  138 , Francesca L Conforti  139 , Amelia Conte  130 , Elisa Conti  140   141 , Massimo Corbo  142 , Stefania Cuccu  131 , Eleonora Dalla Bella  129 , Eustachio D'Errico  143 , Giovanni DeMarco  123 , Raffaele Dubbioso  144 , Carlo Ferrarese  140   141 , Pilar M Ferraro  132 , Massimo Filippi  145   146   147   148 , Nicola Fini  149 , Gianluca Floris  131 , Giuseppe Fuda  123 , Salvatore Gallone  123 , Giulia Gianferrari  149 , Fabio Giannini  128 , Maurizio Grassano  123 , Lucia Greco  150 , Barbara Iazzolino  123 , Alessandro Introna  143 , Vincenzo La Bella  138 , Serena Lattante  151   152 , Giuseppe Lauria  129   153 , Rocco Liguori  154 , Giancarlo Logroscino  155   156 , Francesco O Logullo  157 , Christian Lunetta  150 , Paola Mandich  132   158 , Jessica Mandrioli  149 , Umberto Manera  123 , Fiore Manganelli  144 , Giuseppe Marangi  151   152 , Kalliopi Marinou  159 , Maria Giovanna Marrosu  160 , Ilaria Martinelli  149 , Sonia Messina  161 , Cristina Moglia  123   133 , Gabriele Mora  159 , Lorena Mosca  162 , Maria R Murru  131 , Paola Origone  132 , Carla Passaniti  163 , Cristina Petrelli  157 , Antonio Petrucci  164 , Susanna Pozzi  150 , Maura Pugliatti  165 , Angelo Quattrini  166 , Claudia Ricci  128 , Giulia Riolo  128 , Nilo Riva  166 , Massimo Russo  167 , Mario Sabatelli  168 , Paolina Salamone  123 , Marco Salivetto  150 , Fabrizio Salvi  127 , Marialuisa Santarelli  169 , Luca Sbaiz  126 , Riccardo Sideri  159 , Isabella Simone  143 , Cecilia Simonini  149 , Rossella Spataro  138 , Raffaella Tanel  170 , Gioacchino Tedeschi  163 , Anna Ticca  171 , Antonella Torriello  172 , Stefania Tranquilli  131 , Lucio Tremolizzo  140   141 , Francesca Trojsi  163 , Rosario Vasta  123 , Veria Vacchiano  127 , Giuseppe Vita  167 , Paolo Volanti  173 , Marcella Zollino  174   175 , Elisabetta Zucchi  149
Affiliations

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

Janel O Johnson et al. JAMA Neurol. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Drs Tienari and 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. 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.

Figures

Figure 1.
Figure 1.. Clinical Features of Patients Diagnosed With Juvenile Amyotrophic Lateral Sclerosis
A and B, Tongue wasting and scapular winging in patient 2 carrying the p.Ala20Ser SPTLC1 variant. C and D, Tongue wasting and muscle atrophy of the lower limbs in patient 3 carrying the p.Ser331Tyr SPTLC1 variant. Note the hammertoe deformities of both feet.
Figure 2.
Figure 2.. De Novo Variants of SPTLC1 in Patients Diagnosed With Juvenile Amyotrophic Lateral Sclerosis (ALS)
A-D, Pedigrees of 4 patients diagnosed with juvenile ALS. The variant alleles in SPTLC1 are indicated by vt, and wild-type alleles are indicated by wt. The arrowheads indicate the probands. E, Distribution of SPTLC1 variants detected in patients diagnosed with juvenile ALS. Variants identified in the 3 patients with juvenile ALS are noted in red, and variants previously described to cause hereditary sensory and autonomic neuropathy, type 1A, are shown in green.
Figure 3.
Figure 3.. Photometric and Cell-Based Assays in the Presence of Select SPTLC1 Variants
A, The SPTLC1 enzyme complex activity was determined using a photometric assay measuring the release of free coenzyme A (coA) from the condensation reaction between palmitoyl-CoA and L-serine, L-alanine, and L-glycine. The variant p.Ala20Ser and p.Cys133Trp SPTLC1 complex had increased preference for L-alanine and L-glycine over L-serine compared with the wild-type (WT) SPTLC1 complex. B and C, Mitochondria in HEK293 cells expressing WT, p.Ala20Ser, and p.Cys133Trp were assessed using MitoTracker on a high-content imager. Mitochondrial intensity and mitochondria size were smaller in cells expressing variant protein under standard culture conditions. Supplementation of 100 mM L-serine in the culture media for 48 hours rescued the mitochondrial abnormalities in the p.Ala20Ser and p.Cys133Trp lines.
See this image and copyright information in PMC

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