Recurrent de-novo gain-of-function mutation in SPTLC2 confirms dysregulated sphingolipid production to cause juvenile amyotrophic lateral sclerosis

Maike F. Dohrn, Danique Beijer, Museer A. Lone, Elif Bayraktar, Piraye Oflazer, Rotem Orbach, Sandra Donkervoort, A. Reghan Foley, Aubrey Rose, Michael Lyons, Raymond J. Louie, Kenneth Gable, Teresa Dunn, Sitong Chen, Matt C. Danzi, Matthis Synofzik, Carsten G. Bönnemann, A. Nazll Başak, Thorsten Hornemann, Stephan Zuchner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background Amyotrophic lateral sclerosis (ALS) leads to paralysis and death by progressive degeneration of motor neurons. Recently, specific gain-of-function mutations in SPTLC1 were identified in patients with juvenile form of ALS. SPTLC2 encodes the second catalytic subunit of the serine-palmitoyltransferase (SPT) complex. Methods We used the GENESIS platform to screen 700 ALS whole-genome and whole-exome data sets for variants in SPTLC2. The de-novo status was confirmed by Sanger sequencing. Sphingolipidomics was performed using liquid chromatography and high-resolution mass spectrometry. Results Two unrelated patients presented with early-onset progressive proximal and distal muscle weakness, oral fasciculations, and pyramidal signs. Both patients carried the novel de-novo SPTLC2 mutation, c.203T>G, p.Met68Arg. This variant lies within a single short transmembrane domain of SPTLC2, suggesting that the mutation renders the SPT complex irresponsive to regulation through ORMDL3. Confirming this hypothesis, ceramide and complex sphingolipid levels were significantly increased in patient plasma. Accordingly, excessive sphingolipid production was shown in mutant-expressing human embryonic kindney (HEK) cells. Conclusions Specific gain-of-function mutations in both core subunits affect the homoeostatic control of SPT. SPTLC2 represents a new Mendelian ALS gene, highlighting a key role of dysregulated sphingolipid synthesis in the pathogenesis of juvenile ALS. Given the direct interaction of SPTLC1 and SPTLC2, this knowledge might open new therapeutic avenues for motor neuron diseases.

Original languageEnglish
Pages (from-to)201-205
Number of pages5
JournalJournal of Neurology, Neurosurgery and Psychiatry
Issue number3
StatePublished - 24 Nov 2023
Externally publishedYes


  • ALS


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