Association of Variants in the <i>SPTLC1</i> Gene With Juvenile Amyotrophic Lateral Sclerosis
Janel O. Johnson, Ruth Chia, Danny E. Miller, Rachel Li, Ravindran Kumaran, Yevgeniya Abramzon, Nada F. Alahmady, Alan E. Renton, Simon Topp, J. Raphael Gibbs, Mark Cookson, Marya S. Sabir, Clifton L. Dalgard, Claire Troakes, Ashley R. Jones, Aleksey Shatunov, Alfredo Iacoangeli, Ahmad Al Khleifat, Nicola Ticozzi, Vincenzo Silani, Cinzia Gellera, Ian P. Blair, Carol Dobson‐Stone, John B. Kwok, Emily Bonkowski, Robin Palvadeau, Pentti J. Tienari, Karen 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 A. Glass, Anna I. Scott, Christopher E. Shaw, A. Nazlı Başak, John E. Landers, Adriano Chiò, Thomas O. Crawford, Bradley Smith, Bryan J. Traynor, Bradley Smith, Nicola Ticozzi, Claudia Fallini, Athina Soragia Gkazi, Simon 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 Stević, 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 Sorarú, Kelly L. Williams, Garth A. Nicholson, Ian P. Blair, Claire Leblond-Manry, Guy A. Rouleau, Orla Hardiman, Karen Morrison, Jan H. Veldink, Leonard H. van den Berg, Ammar Al‐Chalabi, Hardev Pall, Pamela J. Shaw, Martin R. Turner
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.