De Novo Variants in SPTLC1 Gene Associated With Juvenile ALS

Diagnostic form with diagnosis Amyotrophic lateral sclerosis (ALS) and pills.
Using exome sequencing, researchers shared results of family-based genetic study on the genetic variants associated with juvenile amyotrophic lateral sclerosis.

Variants in serine palmitoyltransferase, long-chain base subunit 1 (SPTLC1), a gene which encodes to an enzyme involved in the de novo synthesis of sphingolipids, are associated with juvenile amyotrophic lateral sclerosis (ALS), according to study results published in JAMA Neurology.

While the majority of ALS cases occur in individuals older than 40 years, there are rare cases of ALS occurring before 25 years of age, also defined as juvenile ALS. Genetic alterations play a more significant role in juvenile ALS than adult-onset ALS.

The objective of this study was to identify genetic variants associated with juvenile ALS.

The multicenter, family-based genetic study included a whole-exome sequencing of 3 patients diagnosed with juvenile ALS and their unaffected parents. After de novo variants in SPTLC1 were identified in 3 cases (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient), screening of the SPTLC1 gene in a cohort of 63 patients with juvenile ALS from Turkey who had undergone whole-exome sequencing identified a p.Leu39del heterozygous variant in a fourth patient where parental DNA was unavailable.

The protein encoded by SPTLC1 is an essential subunit of serine palmitoyltransferase, the enzyme that catalyzes the first and rate-limiting step in the de novo synthesis of sphingolipids. Prior studies have shown that variants in this gene are associated with autosomal-dominant hereditary sensory and autonomic neuropathy, type 1A.

After establishing the association between variants in SPTLC1 with juvenile ALS, screening 6258 patients with adult-onset ALS identified 20 novel SPTLC1 variants in 23 patients with ALS, suggesting that the genetic causes of juvenile ALS and adult-onset ALS are distinct.

Study limitations included missing DNA from the parents of the fourth patient.

“[O]ur data broaden the phenotype associated with variants in SPTLC1 to include juvenile ALS and implicate sphingolipid metabolism as a pathway in motor neuron disease. Our findings are relevant in light of the fact that nutritional supplementation with serine has been postulated to ameliorate the toxic effect of abnormal sphingolipid metabolites if instituted at an early stage in the disease,” concluded the researchers.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Johnson JO, Chia R, Miller DE, et al. Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis. JAMA Neurol. Published online Aug 30, 2021. doi: 10.1001/jamaneurol.2021.2598