Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis
Authors
Janel O. Johnson, Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
Ruth Chia, Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
Danny E. Miller, Division of Medical Genetics, Department of Medicine, University of Washington, Seattle.
Rachel Li, Department of Pediatrics, Children's Hospital of Richmond at VCU, Richmond, Virginia.
Ravindran Kumaran, Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
Yevgeniya Abramzon, Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.Follow
Nada Alahmady, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Alan E. Renton, Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
Simon D. Topp, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
J Raphael Gibbs, Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
Mark R. Cookson, Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
Marya S. Sabir, Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
Clifton L. Dalgard, Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Claire Troakes, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Ashley R. Jones, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Aleksey Shatunov, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Alfredo Iacoangeli, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Ahmad Al Khleifat, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Nicola Ticozzi, Istituto Auxologico Italiano, IRCCS, Department of Neurology-Stroke Unit and Laboratory of Neuroscience, Milan, Italy.
Vincenzo Silani, Istituto Auxologico Italiano, IRCCS, Department of Neurology-Stroke Unit and Laboratory of Neuroscience, Milan, Italy.
Cinzia Gellera, Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta,' Milan, Italy.
Ian P. Blair, Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia.
Carol Dobson-Stone, The University of Sydney, Brain and Mind Centre and School of Medical Sciences, Faculty of Medicine and Health, Camperdown, Australia.
John B. Kwok, The University of Sydney, Brain and Mind Centre and School of Medical Sciences, Faculty of Medicine and Health, Camperdown, Australia.
Emily S. Bonkowski, Department of Pediatrics, Division of Genetic Medicine, Seattle Children's Hospital, University of Washington, Seattle.
Robin Palvadeau, Suna and Inan Kırac Foundation, Neurodegeneration Research Laboratory, KUTTAM, School of Medicine, Koc University, Istanbul, Turkey.
Pentti J. Tienari, Department of Neurology, Helsinki University Hospital and Translational Immunology Programme, Biomedicum, University of Helsinki, Helsinki, Finland.
Karen E. Morrison, Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, Belfast, United Kingdom.
Pamela J. Shaw, Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom.
Ammar Al-Chalabi, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Robert H. Brown, Department of Neurology, University of Massachusetts Medical School, Worcester.
Andrea Calvo, ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy.
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.
Publication Date
8-31-2021
Publication Title
JAMA neurology
Digital Object Identifier (DOI)
10.1001/jamaneurol.2021.2598
Recommended Citation
Johnson, Janel O.; Chia, Ruth; Miller, Danny E.; Li, Rachel; Kumaran, Ravindran; Abramzon, Yevgeniya; Alahmady, Nada; Renton, Alan E.; Topp, Simon D.; Gibbs, J Raphael; Cookson, Mark R.; Sabir, Marya S.; Dalgard, Clifton L.; Troakes, Claire; Jones, Ashley R.; Shatunov, Aleksey; Iacoangeli, Alfredo; Al Khleifat, Ahmad; Ticozzi, Nicola; Silani, Vincenzo; Gellera, Cinzia; Blair, Ian P.; Dobson-Stone, Carol; Kwok, John B.; Bonkowski, Emily S.; Palvadeau, Robin; Tienari, Pentti J.; Morrison, Karen E.; Shaw, Pamela J.; Al-Chalabi, Ammar; Brown, Robert H.; and Calvo, Andrea, "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis" (2021). Translational Neuroscience. 1042.
https://scholar.barrowneuro.org/neurobiology/1042
