SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease. Recently, several gain-of-function mutations in SPTLC1 were associated with juvenile ALS. SPTLC1 encodes for a subunit of the serine-palmitoyltransferase (SPT) - the rate-limiting enzyme in the de novo synthesis of sphingolipids (SL). SPT activity, and thus SL de novo synthesis, is tightly controlled by a homeostatic feedback mechanism mediated by ORMDL proteins. Here we report a novel SPTLC1p.L38R mutation in a young Chinese girl with a signature of juvenile ALS. The patient presented with muscular weakness and atrophy, tongue tremor and fasciculation, breathing problems and positive pyramidal signs. All SPTLC1-ALS mutations including the SPTLC1 p.L38R are located within a single membrane-spanning domain of the protein and impede the interaction with the regulatory ORMDL subunit of SPT. Pertinent to the altered homeostatic control, lipid analysis showed overall increased SL levels in the patient plasma. An increased SPT activity and SL de novo synthesis was confirmed in p.L38R expressing HEK293 cells. Particularily dihydro-sphingolipids (dhSL) were signficantly increased in patient plasma and p.L38R mutant expressing cells. Increased dhSL formation has been previously linked to neurotoxicity and may be involved in the pathomechanism of SPTLC1-ALS mutations.