ArticleNature medicine2021
Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
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Article in Nature medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers, 1 of them a synthesis that pooled it.
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92citing papers in PubMed, 1 pooled it
12.7field-weighted citation impact, top 1% of its field
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Who cites it
92 citing papers in PubMed, 1 synthesis or guideline pooled it, 150 citations in OpenAlex.
- A molecular systems architecture of neuromuscular junction in amyotrophic lateral sclerosis.NPJ systems biology and applications · 2025Pooled it
- Deletion of exon 2 in ALS-linkedLife science alliance · 2026Article
- Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis.JCI insight · 2026Article
- Convergent human genetic evidence implicates serine biosynthesis in diabetic peripheral neuropathy.medRxiv : the preprint server for health sciences · 2026Article
- Characterization of novel and recurrentJournal of neuromuscular diseases · 2026Article
- Antisense oligonucleotides reverse SPTLC1-related hereditary sensory neuropathy in a mouse model.Brain : a journal of neurology · 2026Article
- Large-scale exome analyses reveal new rare variant contributions in amyotrophic lateral sclerosis.Nature genetics · 2026Article
- Spectrum of dominant Charcot-Marie-Tooth disease due toJournal of neurology, neurosurgery, and psychiatry · 2026Article
- Lipid alterations in hereditary peripheral neuropathies: common mechanisms in disease heterogeneity?Molecular neurodegeneration · 2026Review
- Bi-allelic variants in the ribosomal protein RPS6KC1 cause a complex neurodevelopmental disorder.American journal of human genetics · 2025Article
- Review
- Entering the era of precision medicine to treat amyotrophic lateral sclerosis.Molecular neurodegeneration · 2025Review
- The individual isoforms of ORMDL, the regulatory subunit of serine palmitoyltransferase, have distinctive sensitivities to ceramide.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2025Article
- Altered Lipid Homeostasis in Mutant FUSMolecular neurobiology · 2025Article
- Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review).International journal of molecular medicine · 2025Review
- Use of Proteomics to Explore Biomarkers of Amyotrophic Lateral Sclerosis (ALS): Proof of Principle from Humanized SOD1 Mouse to Human ALS.ACS pharmacology & translational science · 2025Review
- Longitudinal Metabolomics in Amyotrophic Lateral Sclerosis Implicates Impaired Lipid Metabolism.Annals of neurology · 2025Article
- The bioactive sphingolipid playbook. A primer for the uninitiated as well as sphingolipidologists.Journal of lipid research · 2025Review
- Glia phagocytose neuronal sphingolipids to infiltrate developing synapses.bioRxiv : the preprint server for biology · 2025Article
- Gene therapy breakthroughs in ALS: a beacon of hope for 20% of ALS patients.Translational neurodegeneration · 2025Review
32 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
46 authors at 19 institutions in 7 countries.
Payam MohasselNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID http://orcid.org/0000-0001-5313-9514
Sandra Donkervoort *Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Museer A Lone *Institute of Clinical Chemistry, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Matthew Nalls *Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Kenneth Gable *Department of Biochemistry and Molecular Biology, Uniformed Services University of Health Sciences, Bethesda, MD, USA.ORCID http://orcid.org/0000-0002-9122-1006
Sita D Gupta *Department of Biochemistry and Molecular Biology, Uniformed Services University of Health Sciences, Bethesda, MD, USA.ORCID http://orcid.org/0000-0003-2495-1217
A Reghan FoleyNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Ying HuNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Jonas Alex Morales SauteMedical Genetics division and Neurology division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Graduate Program in Medicine: Medical Sciences, and Internal Medicine Department; Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Ana Lucila MoreiraNeurology Department, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
Fernando KokNeurogenetics Outpatient Service, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil and Mendelics, São Paulo, Brazil.
Alessandro IntronaNeurology Unit, Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.ORCID http://orcid.org/0000-0002-3141-6442
Giancarlo LogroscinoNeurology Unit, Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.ORCID http://orcid.org/0000-0003-0423-3242
Christopher GrunseichNeurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Alec R NickollsNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Naemeh PourshafieNeurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Sarah B NeuhausNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Dimah SaadeNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID http://orcid.org/0000-0003-1938-9952
Andrea GangfußDepartment of Paediatric Neurology, Center for Neuromuscular Disorders in Children and Adolescents, University Clinic Essen, University of Duisburg-Essen, Duisburg-Essen, Germany.ORCID http://orcid.org/0000-0002-9975-0092
Heike KölbelDepartment of Paediatric Neurology, Center for Neuromuscular Disorders in Children and Adolescents, University Clinic Essen, University of Duisburg-Essen, Duisburg-Essen, Germany.
Zoe PiccusEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Claire E Le PichonEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.ORCID http://orcid.org/0000-0002-9274-3615
Chiara FiorilloPaediatric Neurology and Muscular Diseases Unit, G. Gaslini Institute and Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health University of Genoa, Genoa, Italy.
Cindy V LyDepartment of Neurology, Washington University in Saint Louis School of Medicine, Saint Louis, MO, USA.
Ana TöpfJohn Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Lauren BradyDivision of Neuromuscular & Neurometabolic Disorders, Department of Paediatrics, McMaster University, Hamilton Health Sciences Centre, Hamilton, Ontario, Canada.
Sabine SpechtJohn Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Aliza ZidellCenter for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack, NJ, USA.
Helio PedroCenter for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Hackensack, NJ, USA.
Eric MittelmannDepartment of Neurology, Hereditary Neuropathy Foundation Center of Excellence, Neuroscience Institute, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Hackensack, NJ, USA.
Florian P ThomasDepartment of Neurology, Hereditary Neuropathy Foundation Center of Excellence, Neuroscience Institute, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Hackensack, NJ, USA.ORCID http://orcid.org/0000-0002-6103-4138
Katherine R ChaoCenter for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Chamindra G KonersmanDepartment of Neurosciences, University of California, San Diego, San Diego, CA, USA.
Megan T ChoGeneDx, Gaithersburg, MD, USA.
Tracy BrandtGeneDx, Gaithersburg, MD, USA.
Volker StraubJohn Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.ORCID http://orcid.org/0000-0001-9046-3540
Anne M ConnollyDepartment of Paediatrics, Neurology Division, Nationwide Children's Hospital, Ohio State University, Columbus, OH, USA.
Ulrike ScharaDepartment of Paediatric Neurology, Center for Neuromuscular Disorders in Children and Adolescents, University Clinic Essen, University of Duisburg-Essen, Duisburg-Essen, Germany.
Andreas RoosDepartment of Paediatric Neurology, Center for Neuromuscular Disorders in Children and Adolescents, University Clinic Essen, University of Duisburg-Essen, Duisburg-Essen, Germany.
Mark TarnopolskyDivision of Neuromuscular & Neurometabolic Disorders, Department of Paediatrics, McMaster University, Hamilton Health Sciences Centre, Hamilton, Ontario, Canada.
Ahmet HökeDepartment of Neurology, Neuromuscular Division, Johns Hopkins School of Medicine, Baltimore, MD, USA.ORCID http://orcid.org/0000-0003-1215-3373
Robert H BrownDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Chia-Hsueh LeeDepartment of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID http://orcid.org/0000-0003-0819-6477
Thorsten HornemannInstitute of Clinical Chemistry, University Hospital Zurich, University of Zurich, Zurich, Switzerland.ORCID http://orcid.org/0000-0002-4218-1087
Teresa M DunnDepartment of Biochemistry and Molecular Biology, Uniformed Services University of Health Sciences, Bethesda, MD, USA. teresa.dunn-giroux@usuhs.edu.ORCID http://orcid.org/0000-0001-9187-8705
Carsten G BönnemannNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. carsten.bonnemann@nih.gov.ORCID http://orcid.org/0000-0002-5930-2324
National Institutes of Health · USHackensack University Medical Center · USUniversity of Duisburg-Essen · DENewcastle University · GBUniformed Services University of the Health Sciences · USHealth Sciences Centre · CAUniversity of Bari Aldo Moro · ITUniversity of Zurich · CHBroad Institute · USHospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo · BRJohns Hopkins University · USNationwide Children's Hospital · USSt. Jude Children's Research Hospital · USUniversidade de São Paulo · BRUniversidade Federal do Rio Grande do Sul · BRUniversity of California San Diego · USUniversity of Genoa · ITUniversity of Massachusetts Chan Medical School · USWashington University in St. Louis · US
Funding
Molecular and Clinical Manifestations of Matrix and Aggregate MyopathiesZIANS003129 · NINDS · NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE · PI BÖNNEMANN, CARSTEN · 2011 to 2025
$52.8MStudies of Hereditary Neurological Disease: Disease MechanismsZIANS003038 · NINDS · NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE · PI FISCHBECK, KENNETH · 2009 to 2023
$19.5MThe neuronal stress response in neurodegenerative disease and painZIAHD008966 · NICHD · EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT · PI LE PICHON, CLAIRE · 2017 to 2025
$17.1MJoint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MA powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9MThe Role of Desoxysphingoid Bases in HSAN1R01NS072446 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI EICHLER, FLORIAN S · 2011 to 2015
$2.1MInvestigating mechanisms of pathogenesis in TBK1-associated amyotrophic lateral sclerosisK08NS107621 · NINDS · WASHINGTON UNIVERSITY · PI LY, CINDY V · 2018 to 2022
$815kOXIDATIVE MARKERS AND MITOCHONDRIAL IMPAIRMENTF32NS010762 · NINDS · WEILL MEDICAL COLLEGE OF CORNELL UNIV · PI ALBERS, DAVID S · 1998 to 1999
–NHGRI NIH HHS R01 HG009141NHGRI NIH HHS UM1 HG008900NINDS NIH HHS F32 NS010762NINDS NIH HHS K08 NS107621NINDS NIH HHS R01 NS072446
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons with sporadic or hereditary occurrence. Age of onset, pattern of motor neuron degeneration and disease progression vary widely among individuals with ALS. Various cellular processes may drive ALS pathomechanisms, but a monogenic direct metabolic disturbance has not been causally linked to ALS. Here we show SPTLC1 variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS. We identified four specific, dominantly acting SPTLC1 variants in seven families manifesting as childhood-onset ALS. These variants disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products. Notably, this is in contrast with SPTLC1 variants that shift SPT amino acid usage from serine to alanine, result in elevated levels of deoxysphingolipids and manifest with the alternate phenotype of hereditary sensory and autonomic neuropathy. We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro. The role of primary metabolic disturbances in ALS has been elusive; this study defines excess sphingolipid biosynthesis as a fundamental metabolic mechanism for motor neuron disease.
Indexed as
AdolescentAdultAllelesAmino Acid SequenceAmyotrophic Lateral SclerosisChildCRISPR-Cas SystemsFemaleGenes, DominantHEK293 CellsHumansMaleMiddle AgedMutationSerine C-PalmitoyltransferaseSphingolipidsSerine C-PalmitoyltransferaseSphingolipidsSPTLC1 protein, human
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