Mutations in the sphingolipid pathway gene SPTLC1 are a cause of amyotrophic lateral sclerosis

SPTLC1 encodes a critical subunit of serine palmitoyltransferase, the enzyme catalyzing the first and rate-limiting step in de novo sphingolipid biosynthesis, and mutations in this gene are known to cause hereditary sensory autonomic neuropathy, type 1A. Using exome sequencing, we identified a de novo coding variant in SPTLC1 in an individual diagnosed with juvenile-onset amyotrophic lateral sclerosis (ALS), and confirmed its pathogenicity by showing elevated plasma levels of neurotoxic deoxymethyl-sphinganine. We also found SPTLC1 mutations in 0.34% of 5,607 ALS cases, and immunohistochemically confirmed the expression of SPTLC1 in spinal cord motor neurons, supporting their role in the pathogenesis of this fatal neurodegenerative disease. Toxicity of deoxymethyl-sphinganine was demonstrated in HEK293FT cells, and could be corrected by L-serine supplementation. Our data broaden the phenotype associated with SPTLC1. Furthermore, nutritional supplementation with serine may be beneficial if instituted at an early stage among patients carrying mutations in SPTLC1.