Mutations in the SPTLC1 gene are a cause of amyotrophic lateral sclerosis that may be amenable to serine supplementation

encodes a critical subunit of serine palmitoyltransferase, the enzyme catalyzing the first and rate-limiting step in sphingolipid biosynthesis, and mutations in this gene are known to cause . Using exome sequencing, we identified a variant in resulting in a p.Ala20Ser amino acid change in an individual diagnosed with juvenile-onset amyotrophic lateral sclerosis (ALS) and confirmed its pathogenicity by showing elevated plasma levels of neurotoxic deoxymethyl-sphinganine. A second case of juvenile-onset ALS arising again from a p.Ala20Ser mutation was later identified, confirming the association of with this form of motor neuron disease. We also found 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 neurological disease. We corrected the toxicity of deoxymethyl-sphinganine in HEK293FT cells using L-serine supplementation. Our data broaden the phenotype associated with and suggest that nutritional supplementation with serine may be beneficial if instituted at an early stage among patients carrying mutations in .