Science News: Childhood Amyotrophic Lateral Sclerosis Caused by Excess Sphingolipid Synthesis

Submitted by: Hristelina Ilieva, MD, PhD

Mohassel P, Donkervoort S, Lone MA, et al. Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis [published online ahead of print, 2021 May 31]. Nat Med. 2021;10.1038

Summary: Amyotrophic lateral sclerosis (ALS) is a devastating disease with poorly understood underlying pathophysiology. This article describes a rare cause of the early onset of motor neuron disease in children due to mutation in SPLTC1, a subunit of the SPT (serine palmitoyltransferase). SPT is a key enzyme in sphingolipid metabolism. Mammalian SPT belongs to the family of pyridoxal phosphate (vit B6) dependent alpha-oxoamine synthases. A mutant subunit was identified in children with this disorder. Children developed toe walking and spasticity starting around 4 years of age and lived from 5 to 20 years. This mutation causes overproduction of sphingolipids. Sphingosine levels could be normalized by silencing approaches. This represents a potential therapy for this group of patients.

Comments: Better understanding the underlying mechanisms of disease may lead to more effective treatments. ALS is a heterogenous disease with multiple known and unknown pathologic contributors. The role of sphingolipids in ALS pathology is largely unknown and may be of clinical benefit for many patient populations.