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

Janel Johnson , Ruth Chia , Danny Miller (1) , Rachel Li , Ravindran Kumaran , Yevgeniya Abramzon , Nada Alahmady , Alan Renton (2) , Simon Topp , J Raphael Gibbs , Mark Cookson (3) , Marya Sabir , Clifton Dalgard , Claire Troakes (4) , Ashley Jones , Aleksey Shatunov , Alfredo Iacoangeli , Ahmad Al Khleifat , Nicola Ticozzi , Vincenzo Silani , Cinzia Gellera , Ian Blair , Carol Dobson-Stone , John Kwok , Emily Bonkowski , Robin Palvadeau , Pentti Tienari , Karen Morrison , Pamela Shaw , Ammar Al-Chalabi , Robert Brown , Andrea Calvo , Gabriele Mora , Hind Al-Saif , Marc Gotkine , Fawn Leigh , Irene Chang , Seth Perlman , Ian Glass , Anna Scott , Christopher Shaw , a Nazli Basak , John Landers , Adriano Chiò , Thomas Crawford , Bradley Smith , Bryan Traynor , Claudia Fallini , Athina Soragia Gkazi , Emma Scotter , Kevin Kenna , Pamela Keagle , Cinzia Tiloca , Caroline Vance , Claudia Colombrita , Andrew King , Viviana Pensato , Barbara Castellotti , Frank Baas , Anneloor ten Asbroek , Diane Mckenna-Yasek , Russell Mclaughlin , Meraida Polak , Seneshaw Asress , Jesús Esteban-Pérez , Zorica Stevic , Sandra d'Alfonso , Letizia Mazzini , Giacomo 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 Williams , Garth Nicholson , Claire Leblond-Manry , Guy Rouleau , Orla Hardiman , Jan Veldink , Leonard van den Berg , Hardev Pall , Martin Turner , Kevin Talbot , Franco Taroni , Alberto García-Redondo , Zheyang Wu , Jonathan Glass , Antonia Ratti , Adelani Adeleye , Anthony Soltis , Camille Alba , Coralie Viollet , Dagmar Bacikova , Daniel Hupalo , Gauthaman Sukumar , Harvey Pollard , Matthew Wilkerson , Elisa Mcgrath Martinez , Sarah Ahmed , Sampath Arepalli , Robert Baloh , Robert Bowser , Christopher Brady , Alexis Brice , James Broach , Roy Campbell , William Camu (5, 6) , John Cooper-Knock , Jinhui Ding , Carsten Drepper , Vivian Drory , Travis Dunckley , John Eicher , Bryce England , Faraz Faghri , Eva Feldman , Mary Kay Floeter , Pietro Fratta , Joshua Geiger , Glenn Gerhard , Summer Gibson , John Hardy , Matthew Harms , Terry Heiman-Patterson , Dena Hernandez , Lilja Jansson , Janine Kirby , Neil Kowall , Hannu Laaksovirta , Natalie Landeck , Francesco Landi , Isabelle Le Ber , Serge Lumbroso (7, 6) , Daniel Macgowan , Nicholas Maragakis , Kevin Mouzat (7, 6) , Natalie Murphy , Liisa Myllykangas , Mike Nalls , Richard Orrell , Lyle Ostrow , Roger Pamphlett , Stuart Pickering-Brown , Erik Pioro , Olga Pletnikova , Hannah Pliner , Stefan Pulst , John Ravits , Alberto Rivera , Wim Robberecht , Ekaterina Rogaeva , Sara Rollinson , Jeffrey Rothstein , Sonja Scholz , Michael Sendtner , Katie Sidle , Zachary Simmons , Andrew Singleton , Nathan Smith , David Stone , Juan Troncoso , Miko Valori , Philip van Damme , Vivianna van Deerlin , Ludo van den Bosch , Lorne Zinman , Stefania Angelocola , Francesco Ausiello , Marco Barberis , Ilaria Bartolomei , Stefania Battistini , Enrica Bersano , Giulia Bisogni , Giuseppe Borghero , Maura Brunetti , Corrado Cabona , Fabrizio Canale , Antonio Canosa , Teresa Cantisani , Margherita Capasso , Claudia Caponnetto , Patrizio Cardinali , Paola Carrera , Federico Casale , Tiziana Colletti , Francesca Conforti , Amelia Conte , Elisa Conti , Massimo Corbo , Stefania Cuccu , Eleonora Dalla Bella , Eustachio d'Errico , Giovanni Demarco , Raffaele Dubbioso , Carlo Ferrarese , Pilar 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 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 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 , J. Raphael Gibbs , A. Nazli Basak , Sandra D’alfonso , Eustachio D’errico

1 HEC Montréal - HEC Montréal
2 UCL - University College of London [London]
3 NIH - National Institutes of Health [Bethesda, MD, USA]
4 King‘s College London
5 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
6 INM - Institut des Neurosciences de Montpellier
7 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes

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.

Domaines: Médecine humaine et pathologie; Neurosciences [q-bio.NC]

Janel Johnson, Ruth Chia, Danny Miller, Rachel Li, Ravindran Kumaran, et al.. Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis. JAMA neurology, 2021, 78 (10), pp.1236. ⟨10.1001/jamaneurol.2021.2598⟩. ⟨hal-03638943⟩