NTRK1 – Congenital Insensitivity to Pain with Anhidrosis (HSAN IV)

Congenital insensitivity to pain with anhidrosis (HSAN IV; MONDO:0009746) is an autosomal recessive neurodevelopmental disorder caused by biallelic loss-of-function mutations in the NTRK1 gene (HGNC:8031), which encodes the high-affinity receptor TrkA for nerve growth factor. Affected individuals exhibit absence of pain and temperature sensation, self-mutilation, anhidrosis, and variable intellectual disability.

Extensive genetic evidence from multiple cohorts supports a definitive association. Over 23 unrelated families [PMID:10982191] and seven additional pedigrees [PMID:10330344] have been reported with cosegregation of biallelic NTRK1 variants, including segregation in at least 19 affected relatives [PMID:10982191].

Variants span missense substitutions, frameshifts, nonsense, and splice-site mutations, predominantly clustering in the tyrosine kinase domain. A recurrent variant, c.2303C>T (p.Pro768Leu), has been observed in multiple ethnicities with milder phenotypes, while canonical splice mutations such as c.851-33T>A underlie founder haplotypes in Asian populations.

Functional studies uniformly demonstrate loss of TrkA activity. Autophosphorylation assays of mutant receptors reveal abrogated NGF-stimulated kinase activation [PMID:11159935], and misfolding/aggregation defects have been shown to disrupt autophagic flux in neuronal models [PMID:27551041]. PC12 differentiation assays confirm the inability of mutant TrkA to support NGF-dependent survival and neurite outgrowth.

No conflicting evidence has been reported; all pathogenic variants result in loss of NGF–TrkA signaling concordant with the human phenotype. The collective genetic and experimental data meet ClinGen definitive criteria for gene–disease validity.

Key take-home: Clinical testing for NTRK1 variants enables early diagnosis of HSAN IV, guiding management of temperature regulation and injury prevention.

References

• American journal of human genetics • 1999 • Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor PMID:10330344
• Human genetics • 2000 • Mutation and polymorphism analysis of the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor in congenital insensitivity to pain with anhidrosis (CIPA) families PMID:10982191
• Human molecular genetics • 2001 • Congenital insensitivity to pain with anhidrosis: effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor PMID:11159935
• The Journal of biological chemistry • 2016 • Mutations in TrkA Causing Congenital Insensitivity to Pain with Anhidrosis (CIPA) Induce Misfolding, Aggregation, and Mutation-dependent Neurodegeneration by Dysfunction of the Autophagic Flux PMID:27551041

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