SPTLC2 – Hereditary Sensory and Autonomic Neuropathy Type 1C

Hereditary sensory and autonomic neuropathy type 1C (HSAN1C; MONDO:0013337) is an autosomal dominant peripheral neuropathy characterized by distal sensory loss, small-fiber degeneration, and variable motor involvement. The disorder arises from pathogenic variants in SPTLC2 (HGNC:11278), which encodes the 3-ketodihydrosphingosine synthase subunit of serine palmitoyltransferase (SPT). Clinically, HSAN1C patients present with neurodegeneration (HP:0002180) manifesting as sensory-predominant neuropathy often accompanied by ulcerations and mild motor deficits.

Genetic evidence for SPTLC2 in HSAN1C includes at least 10 unrelated probands (PMID:29042446; PMID:26573920; PMID:30955194), with segregation documented in 7 additional affected relatives (PMID:26573920; PMID:30955194). All families exhibited autosomal dominant inheritance with complete penetrance by late adulthood.

The variant spectrum is dominated by missense changes altering substrate specificity. The recurrent c.547C>T (p.Arg183Trp) substitution has been described in two kindreds with late-onset sensory neuropathy (PMID:26573920). Other pathogenic alleles include c.529A>G (p.Asn177Asp) in a German pedigree (PMID:30955194) and c.1151C>T (p.Ser384Phe) in independent panel-based sequencing (PMID:32730653). These variants cluster near phosphorylation or substrate-binding motifs.

Functional studies demonstrate that HSAN1C-causing SPTLC2 variants induce substrate promiscuity, favoring L-alanine or glycine over L-serine and leading to accumulation of neurotoxic 1-deoxysphingolipids. Cell-based assays show increased 1-deoxySL production and altered canonical SPT activity for p.Arg183Trp, p.Asn177Asp, and p.Ser384Phe alleles (PMID:26573920; PMID:30955194). Lipidomic profiling in patients corroborates these findings.

A single-patient case report of oral L-serine supplementation (up to 400 mg/kg/day) demonstrated robust lowering of plasma 1-deoxySL without major metabolic disturbance, supporting a targeted treatment strategy for HSAN1C (PMID:29042446).

No studies to date have refuted the gene–disease relationship or implicated alternative phenotypes for SPTLC2 in HSAN1C. Collectively, the genetic and experimental data fulfill ClinGen criteria for a strong gene–disease association.

Key take-home: SPTLC2 pathogenic variants cause autosomal dominant HSAN1C via gain-of-function substrate shifts; genetic testing and trial of L-serine supplementation can guide diagnosis and management.

References

• Cold Spring Harbor Molecular Case Studies • 2017 • Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C PMID:29042446
• Neuromolecular Medicine • 2016 • The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory Neuropathy PMID:26573920
• Neuromolecular Medicine • 2019 • A Novel Variant (Asn177Asp) in SPTLC2 Causing Hereditary Sensory Autonomic Neuropathy Type 1C PMID:30955194
• Annals of Clinical and Translational Neurology • 2020 • Demyelination in hereditary sensory neuropathy type-1C PMID:32730653

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