Adult onset neurodegenerative disorder

Gene: SPTLC1

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 11 Mar 2026, 10:56 a.m. | Last Modified: 11 Mar 2026, 10:56 a.m.

Panel Version: 8.15

Green List (high evidence)

Comment on list classification: There are at least 11 unrelated cases with juvenile-onset ALS with monoallelic SPTLC1 variants (age of onset between 3-16 years). Variants were confirmed as de novo in 9/11 families. According to functional studies, ALS causing variants tend to cluster in the N-terminal transmembrane domain. Based on the available evidence, SPTLC1 fits into the scope of this panel and should be rated Green for Adult onset neurodegenerative disorder.

Created: 13 Oct 2025, 1:55 p.m. | Last Modified: 13 Oct 2025, 1:55 p.m.

Panel Version: 8.3

As reviewed by James Polke, SPTLC1 variants are associated with juvenile-onset amyotrophic lateral sclerosis. There are at least 11 unrelated cases with juvenile ALS with monoallelic SPTLC1 variants:

PMID: 34059824 Mohassel et al., 2021
11 patients from seven independent families with 4 different SPTLC1 variants, with juvenile ALS (age of onset 3-16 years). Affected individuals presented with abnormal gait, toe walking, lower extremities spasticity, respiratory insufficiency, and progressive weakness. EMG signal amplitude and duration were elevated in 9/11 patients tested; compound muscle action potential in motor NCS was low in all 11 patients.
Variants were either de novo (Families 1-6) or inherited in an autosomal dominant manner (Family 7), none of them present in gnomAD v4. Reported variants: c.58G>T, p.A20S; c.68A>T p.Y23F; c.115_117delCTT p.L39del; c.118_123delTTCTCT p.F40_S41del.

PMID: 34459874 Johnson et al., 2021
Identified pathogenic SPTLC1 variants in 4 unrelated patients with juvenile ALS (age of onset: 4-15 years). Variants identified: p.Ala20Ser (2 patients), p.Ser331Tyr, p.Leu39del - Method: WES; confirmed de novo in 3 / 4 individuals.

Functional evidence:
Evidence for pathogenicity of variants: PMID: 35900868 Lone et al., 2022. Authors tested HSAN1 variants C133W and S331F, and juvenile ALS variants Y23F, L39del, F40S41del. Study showed that pathogenic SPTLC1 ALS-related alleles disrupt the normal regulation of SPT, leading to increased synthesis of sphingolipids and potentially damaging motor neurons. ALS causing variants tend to cluster in the N-terminal transmembrane domain (TMD); variants in the cytosolic domain are largely associated with HSAN1.
Mouse model: PMID: 40027730 Pant et al. 2025 (preprint) - novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in Sptlc1. Heterozygous mice did not develop motor defects or ALS-like neuropathology, but homozygous mutants died prematurely.

SPTLC1 is associated with AD Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285 and AD Neuropathy, hereditary sensory and autonomic, type IA OMIM:162400 (accessed 10th Oct 2025).

Created: 10 Oct 2025, 10:05 a.m. | Last Modified: 13 Oct 2025, 1:49 p.m.

Panel Version: 8.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285; amyotrophic lateral sclerosis 27, juvenile, MONDO:0859529

Publications

• 34059824
• 34459874
• 35900868
• 40027730

Green List (high evidence)

SPTLC1 previously associated with HSN1A but variants in these two publications associated with juvenile ALS. 34059824 and 35900868 propose a distinct pathomechanism of juvenile ALS variants (increased sphinganine systhesis) compared to HSN1A variants (shift to deoxysphinganine synthesis). At least 5 different variants now reported, almost all de-novo, but one family in 34059824 with p.Leu39del inherited from father with mild sensorimotor axonal neuropathy. Juvenile onset but inclusion on this adult panel in-line with current inclusion of ALS2 and SETX which also cause early onset ALS.

No evidence that LoF variants cause HSN1A or juvenile ALS - GOF mechanisms demonstrated.
Sources: NHS GMS

Created: 30 Aug 2022, 11:19 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Juvenile ALS

Publications

• 34059824
• 34459874
• 35627278
• 35900868

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments