Recurrent de novo SPTLC2variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motor neurons with varying ages of onset, progression and pathomechanisms. Monogenic childhood-onset ALS, although rare, forms an important subgroup of ALS. We recently reported specific SPTLC1variants resulting in sphingolipid overproduction as a cause for juvenile ALS. Here, we report six patients from six independent families with a recurrent, de novo, heterozygous variant in SPTLC2c.778G>A [p.Glu260Lys] manifesting with juvenile ALS.MethodsClinical examination of the patients along with ancillary and genetic testing, followed by biochemical investigation of patients’ blood and fibroblasts, was performed.ResultsAll patients presented with early-childhood-onset progressive weakness, with signs and symptoms of upper and lower motor neuron degeneration in multiple myotomes, without sensory neuropathy. These findings were supported on ancillary testing including nerve conduction studies and electromyography, muscle biopsies and muscle ultrasound studies. Biochemical investigations in plasma and fibroblasts showed elevated levels of ceramides and unrestrained de novo sphingolipid synthesis. Our studies indicate that SPTLC2variant [c.778G>A, p.Glu260Lys] acts distinctly from hereditary sensory and autonomic neuropathy (HSAN)-causing SPTLC2variants by causing excess canonical sphingolipid biosynthesis, similar to the recently reported SPTLC1ALS associated pathogenic variants. Our studies also indicate that serine supplementation, which is a therapeutic in SPTLC1and SPTCL2-associated HSAN, is expected to exacerbate the excess sphingolipid synthesis in serine palmitoyltransferase (SPT)-associated ALS.ConclusionsSPTLC2is the second SPT-associated gene that underlies monogenic, juvenile ALS and further establishes alterations of sphingolipid metabolism in motor neuron disease pathogenesis. Our findings also have important therapeutic implications: serine supplementation must be avoided in SPT-associated ALS, as it is expected to drive pathogenesis further.