Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis

Payam Mohassel, Sandra Donkervoort, Museer A. Lone, Matthew Nalls, Kenneth Gable, Sita D. Gupta, A. Reghan Foley, Ying Hu, Jonas Alex Morales Saute, Ana Lucila Moreira, Fernando Kok, Alessandro Introna, Giancarlo Logroscino, Christopher Grunseich, Alec R. Nickolls, Naemeh Pourshafie, Sarah B. Neuhaus, Dimah Saade, Andrea Gangfuß, Heike KölbelZoe Piccus, Claire E. Le Pichon, Chiara Fiorillo, Cindy V. Ly, Ana Töpf, Lauren Brady, Sabine Specht, Aliza Zidell, Helio Pedro, Eric Mittelmann, Florian P. Thomas, Katherine R. Chao, Chamindra G. Konersman, Megan T. Cho, Tracy Brandt, Volker Straub, Anne M. Connolly, Ulrike Schara, Andreas Roos, Mark Tarnopolsky, Ahmet Höke, Robert H. Brown, Chia Hsueh Lee, Thorsten Hornemann, Teresa M. Dunn, Carsten G. Bönnemann

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1197-1204
Number of pages8
JournalNature medicine
Issue number7
StatePublished - Jul 2021

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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