HSAN-4

NTRK1 | 1996

What Is HSAN-4?

HSAN-4 is a type of CMT caused by autosomal recessive mutations in the NTRK1 gene. This gene provides instructions for making the high-affinity nerve growth factor receptor TrkA, which is essential for the development and survival of pain- and temperature-sensing nerve cells. Mutations in the NTRK1 gene disrupt this function, leading to impaired nerve signal transmission.

HSAN-4 is autosomal recessive, meaning that both copies of the gene must have a mutation to cause this subtype.

Clinical Features

Symptoms of HSAN-4 are present from birth and center on a congenital inability to sense pain together with an inability to sweat. This subtype affects the small sensory and autonomic nerve fibers. Nerve conduction of the large fibers may be relatively preserved, reflecting the axonal and small-fiber nature of the disease.

HSAN-4 symptoms may include:

  • Congenital insensitivity to pain
  • Inability to sweat (anhidrosis)
  • Recurrent episodes of unexplained fever
  • Reduced temperature sensation
  • Repeated injuries that go unnoticed due to absent pain
  • Cognitive impairment in some individuals
  • Foot drop
  • Additional symptoms not listed here

Disease Course

HSAN-4 is present from birth and carries serious risks, particularly in early childhood. Recurrent episodes of high fever from the inability to sweat can be life-threatening in infancy, and the absence of pain sensation leads to repeated unrecognized injuries. With careful management of temperature regulation and injury prevention, individuals can survive into adulthood, though the disease course remains variable.

Clinical Basics

Subtype
HSAN-4

Classification
HSAN

Subtype Alias
CIPA

Neuropathy Type
Axonal

Inheritance Pattern
autosomal recessive

Genetic Context

HGNC-Approved Gene Symbol
NTRK1

Gene Full Name
Neurotrophic Receptor Tyrosine Kinase 1

Chromosome
1q23.1

Zygosity of Responsible Variant
Homozygous or Compound Heterozygous

Variant Mechanism

Loss of Function (LoF)

Details

Mechanistic basis:
Biallelic

Confidence:
High

Prediction:
The literature predicts a biallelic loss-of-function mechanism for HSAN-4: recessive NTRK1 mutations abolish or reduce TrkA receptor tyrosine kinase activity, disrupting NGF signaling required for nociceptive sensory and sympathetic neurons. Because the mutant receptor loses activity rather than disrupting wild-type, restored functional TrkA is predicted to rescue, consistent with recessive loss of function.

Rationale:
Biallelic NTRK1 loss-of-function alleles abolish or reduce TrkA kinase activity and NGF signaling, so restored wild-type TrkA is predicted to rescue rather than the mutant disrupting wild-type: a recessive loss of function.

ClinVar Pathogenic Variants

View HSAN-4 ClinVar Variants

ClinGen Curation

View NTRK1 ClinGen Curation

HSAN-4 OMIM Entry

HSAN-4 OMIM

NTRK1 OMIM Entry

NTRK1 OMIM

More Info

HSAN-4 Research Opportunity

CMT Natural History Study

Original Discovery Publication

Publication Title

Mutations in the TRKA/NGF Receptor Gene in Patients with Congenital Insensitivity to Pain with Anhidrosis

Authors

Indo, Y., Tsuruta, M., Hayashida, Y., Karim, M. A., Ohta, K., Kawano, T., Mitsubuchi, H., Tonoki, H., Awaya, Y., & Matsuda, I.

Publication Date
August 1, 1996

DOI
10.1038/ng0896-485

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

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