SPTLC1 – Hereditary Sensory and Autonomic Neuropathy Type 1

Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is an autosomal dominant, ulceromutilating peripheral neuropathy characterized by progressive distal sensory loss, pain insensitivity, and motor involvement leading to foot ulcers and amputations. The locus was mapped to chromosome 9q22.1-22.3 and mutations in SPTLC1, encoding the long-chain base subunit 1 of serine palmitoyltransferase, were identified as the genetic cause of HSAN1. SPTLC1 mediates the first and rate-limiting step of de novo sphingolipid synthesis, explaining the neuropathic phenotype via disrupted lipid metabolism.

Genetic evidence for the association is robust. Mutation screening in 11 HSAN1 families revealed three missense mutations in exon 5 and exon 6 of SPTLC1 segregating with disease (C133Y, C133W, V144D) (PMID:11242114). Haplotype analysis across six families carrying the recurrent c.399T>G (p.Cys133Trp) variant demonstrated a common founder in southern England (PMID:11479835). Multiple independent reports describe over 30 distinct missense variants in more than 200 affected individuals, including the novel c.1160G>C (p.Gly387Ala) in twin sisters with severe phenotype (PMID:15037712) and recurrent S331F/Y substitutions with diffuse muscle wasting and growth retardation (PMID:23454272).

The variant spectrum is dominated by missense changes clustering in key functional domains. Over 25 pathogenic alleles affect residues Cys133, Val144, Ser331 and Gly387, with no reported loss‐of‐function or truncating mutations, supporting a dominant‐negative or gain‐of‐function mechanism. Founder alleles (p.Cys133Trp) recur in European pedigrees, whereas variants at Ser331 drive a particularly severe, early-onset syndrome. One representative allele is c.1160G>C (p.Gly387Ala), demonstrating phenotypic consistency in twin probands (PMID:15037712).

Functional studies confirm a dominant‐negative mechanism. In patient lymphoblasts and CHO-LCB1–deficient cells, C133Y and C133W mutants reduce SPT activity, impair sphingolipid synthesis, and inhibit wild-type enzyme via subunit interaction (PMID:12417569). Mutant overexpression shifts substrate specificity toward L-alanine, generating neurotoxic deoxy-sphingoid bases that accumulate in plasma and sensory neurons, causing neurite degeneration in vitro (PMID:20097765). Animal models in Drosophila and C. elegans recapitulate sensory deficits and demonstrate rescue by modulation of ER–Golgi trafficking and wild-type allele overexpression.

There is no credible conflicting evidence; all reports support an autosomal dominant gain-of-function mechanism. No refuting studies or alternative phenotypes have been assigned to SPTLC1 in the context of HSAN1.

In summary, SPTLC1 mutations cause HSAN1 through dominant‐negative and gain-of-function effects on serine palmitoyltransferase, leading to toxic lipid metabolite accumulation and sensory neuron degeneration. Genetic testing for SPTLC1 missense variants supports diagnosis, family counseling, and may guide future substrate-modulation therapies.

References

• Neurology • 2004 • SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I. PMID:15037712
• American Journal of Human Genetics • 2001 • Hereditary sensory neuropathy type I: haplotype analysis shows founders in southern England and Europe. PMID:11479835
• Nature Genetics • 2001 • Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. PMID:11242114
• The Journal of Clinical Investigation • 2002 • Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis. PMID:12417569
• The Journal of Biological Chemistry • 2010 • Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. PMID:20097765
• Brain: A Journal of Neurology • 2006 • Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I). PMID:16364956

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