HSAN-2D

SCN9A | 2013

What Is HSAN-2D?

HSAN-2D is a type of CMT caused by autosomal recessive mutations in the SCN9A gene. This gene provides instructions for making part of a sodium channel that is essential for transmitting pain signals along sensory nerves. Mutations in the SCN9A gene disrupt this function, leading to impaired nerve signal transmission.

HSAN-2D is autosomal recessive, meaning that both copies of the gene must have a mutation to cause this subtype.

Clinical Features

The age of symptom onset in HSAN-2D 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.

HSAN-2D 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

HSAN-2D 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
HSAN-2D

Classification
HSAN

Neuropathy Type
Axonal

Inheritance Pattern
autosomal recessive

Genetic Context

HGNC-Approved Gene Symbol
SCN9A

Gene Full Name
sodium voltage-gated channel alpha subunit 9

Chromosome
2q24.3

Zygosity of Responsible Variant
Homozygous or Compound Heterozygous

Variant Mechanism

Loss of Function (LoF)

Details

Mechanistic basis:
Complete loss

Confidence:
High

Prediction:
Two inactive copies of a single sodium channel gene account for HSAN-2D, and the evidence predicts biallelic loss of function: nonsense, frameshift, and splice alleles in SCN9A eliminate Nav1.7 from nociceptors and sympathetic ganglion neurons, removing the amplifier that brings small-fiber terminals to action potential threshold. Anosmia accompanies the pain insensitivity because the same channel is required in olfactory sensory neurons. Wild-type Nav1.7 add-back is predicted to rescue.

Rationale:
Direction of effect separates the SCN9A diseases cleanly: channel-inactivating alleles in two copies abolish pain sensation from birth, while heterozygous alleles that slow inactivation or shift activation produce erythromelalgia and paroxysmal extreme pain disorder. HSAN-2D falls on the inactivating side, and relatives carrying a single null allele have normal pain perception.

ClinVar Pathogenic Variants

View SCN9A ClinVar Variants

HSAN-2D OMIM Entry

HSAN-2D OMIM

SCN9A OMIM Entry

SCN9A OMIM

More Info

HSAN-2D Research Opportunity

CMT Natural History Study

Original Discovery Publication

Publication Title

Hereditary Sensory and Autonomic Neuropathy Type IID Caused by an SCN9A Mutation

Authors

Yuan, J., Matsuura, E., Higuchi, Y., Hashiguchi, A., Nakamura, T., Nozuma, S., Sakiyama, Y., Yoshimura, A., Izumo, S., & Takashima, H.

Publication Date
April 17, 2013

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

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