Congenital insensitivity to pain with anhidrosis (
CIPA), also referred to as
hereditary sensory and autonomic neuropathy type IV (
HSAN-IV), is an autosomal recessive hereditary disorder characterized by recurrent episodic
fever,
anhidrosis (inability to sweat), absence of reaction to noxious stimuli,
self-mutilating behavior, and
mental retardation. The TRKA (NTRK1) gene located on chromosome 1 (1q21-q22), consists of 17 exons and spans at least 23 kb. TRKA encodes the
receptor tyrosine kinase (RTK) for
nerve growth factor (
NGF) and is the gene responsible for
CIPA. Defects in
NGF signal transduction at the
TRKA receptor lead to failure to support survival of sympathetic ganglion neurons and nociceptive sensory neurons derived from the neural crest. Thirty-seven different TRKA mutations, identified in patients in various countries, including nine frameshift, seven nonsense, seven splice, and 14 missense mutations, are distributed in an extracellular domain involved in
NGF binding, as well as in the intracellular signal-transduction domain. Extensive analysis of
CIPA mutations and associated intragenic polymorphisms should facilitate detection of
CIPA mutations and aid in the diagnosis and genetic counseling of this painless but severe
genetic disorder with devastating complications. In addition, naturally occurring TRKA missense mutations with loss of function provide considerable insight into the structure-function relationship in the RTK family. Further, molecular pathology of
CIPA would provide unique opportunities to explore critical roles of the autonomic sympathetic nervous system as well as peripheral sensory nervous system that transmit noxious stimuli in humans.