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:
The literature predicts a neomorphic gain-of-function mechanism for HSN-1C: dominant SPTLC2 missense mutations cause serine palmitoyltransferase to use alanine and glycine instead of serine and produce neurotoxic 1-deoxysphingolipids. Added wild-type SPT does not rescue because the toxicity comes from the aberrant lipid species rather than lost normal activity, supporting a gain of a novel toxic function over haploinsufficiency or a dominant-negative effect.

Rationale:
Dominant SPTLC2 missense alleles shift serine palmitoyltransferase substrate specificity toward alanine and glycine and generate neurotoxic 1-deoxysphingolipids on their own, a novel activity that added wild-type does not rescue, distinguishing it from haploinsufficiency or dominant-negative interference: a neomorphic gain of function.

ClinVar Pathogenic Variants

View HSN-1C 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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