Juvenile amyotrophic lateral sclerosis (JALS) is a rare and severe motor neuron disease defined by an onset before the age of 25 with currently no available therapy. Only a few genes have been linked to JALS such as ALS2, FUS, SETX, SPG11, SIGMAR1, and more recently SPTLC1. This gene encodes one of the subunits of serine palmitoyltransferase (SPT), which is the first enzyme for de novo sphingolipid biosynthesis.1 Initially, SPTLC1 was a known cause of hereditary sensory and autonomic neuropathy, type 1A.2 In 2021, Johnson et al 3 and Mohassel et al 4 extended the phenotype associated with this gene by reporting several mutations of SPTLC1 in patients with JALS.

We performed molecular analysis of 1130 patients with ALS, with 50 of them meeting the criteria for juvenile ALS. Plasma lipid profile of patients with SPTLC1 mutation were analysed using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and tandem mass spectrometry (MS/MS).

We identified a total of five individuals harbouring the heterozygous already known pathogenic SPTLC1 (NM_006415.4): c.115_117del, p.(Leu39del) variant (figure 1). Analysis of the single-nucleotide polymorphisms (SNPs) surrounding the mutation allowed us to confidently exclude the possibility of a founder effect (online supplemental material 1).

[jnnp-2023-331753supp001.pdf]

Identification of SPTLC1 p.Leu39del mutation in four non-related families. (A) Pedigree showing segregation of the disease with p.Leu39del mutation. (B) Deficit of intrinsic hand muscles and wrist extensors with atrophy and tongue muscle wasting in patient 3B. (C) Plasma lipid profile of patients with SPTLC1 p.Leu39del mutation. CER, ceramide; SM, sphingomyelin; N, normal range; high CER or SM levels are shown in red and low levels in light blue. (D) In silico modelling of missense SPTLC1 variants. Homology model of the human SPT heterodimer wild-type (on the left) and with Leu39del (on the right) …