HSN-1C

SPTLC2 | 2010

What Is HSN-1C?

HSN-1C is a type of CMT caused by autosomal dominant mutations in the SPTLC2 gene. This gene provides instructions for making part of an enzyme involved in the production of sphingolipids, a class of fats essential to nerve cell membranes. Mutations in the SPTLC2 gene disrupt this function, leading to impaired nerve signal transmission.

HSN-1C is autosomal dominant, meaning that just one of the gene’s two copies needs a mutation to cause this subtype.

Clinical Features

The age of symptom onset in HSN-1C is variable, ranging from childhood to adulthood. The disease involves loss of sensation that begins in the hands and feet (glove-and-stocking distribution) and progresses over time towards the center of the body. Nerve conduction studies usually show somewhat slowed conduction velocities and reduced amplitudes, consistent with an axonal form of CMT.

HSN-1C symptoms may include:

  • Progressive loss of sensation in the feet and hands
  • Loss of pain and temperature sensation
  • Reduced or absent reflexes
  • Foot deformities, including high arches, and hammertoes (clawed toes)
  • Distal weakness that develops as the disease progresses
  • Foot drop
  • Additional symptoms not listed here

Disease Course

HSN-1C shows wide variability in severity and progression. Some individuals are mildly affected, while others develop a more severe disease. Disease progression is generally slow, and life expectancy is not reduced.

Clinical Basics

Subtype
HSN-1C

Classification
HSN

Neuropathy Type
Axonal

Inheritance Pattern
autosomal dominant

Genetic Context

HGNC-Approved Gene Symbol
SPTLC2

Gene Full Name
serine palmitoyltransferase long chain base subunit 2

Chromosome
14q24.3

Zygosity of Responsible Variant
Heterozygous

Variant Mechanism

Toxic Gain of Function (GoF)

Details

Mechanistic basis:
Neomorphic

Confidence:
High

Prediction:
In HSN-1C the literature places the neomorphic gain in the catalytic half of the enzyme: SPTLC2 carries the pyridoxal-5'-phosphate-binding lysine of the serine palmitoyltransferase heterodimer, and dominant missense substitutions there widen the amino acid preference of the active site to include alanine and glycine. The condensation reaction then yields 1-deoxysphingolipids in place of canonical sphingoid bases. Because SPTLC1 contributes the non-catalytic subunit of the same enzyme, alleles in either gene converge on one metabolic lesion.

Rationale:
SPTLC2 substitutions act on the chemistry itself rather than on an accessory subunit, which is why the metabolic readout is so clean. Excess L-serine lowers circulating 1-deoxysphingolipids in this disease group by outcompeting alanine at a mutant active site, and that response is diagnostic: an enzyme that had simply stopped working would generate no such metabolite to lower.

ClinVar Pathogenic Variants

View SPTLC2 ClinVar Variants

HSN-1C OMIM Entry

HSN-1C OMIM

SPTLC2 OMIM Entry

SPTLC2 OMIM

More Info

HSN-1C Research Opportunity

CMT Natural History Study

Original Discovery Publication

Publication Title

Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I

Authors

Rotthier, A., Auer-Grumbach, M., Janssens, K., Baets, J., Penno, A., Almeida-Souza, L.

Publication Date
October 8, 2010

Updated: July 18, 2026 | By: K. Raymond

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