Decreased tyrosine kinase C expression may reflect developmental abnormalities in Hirschsprung's disease and idiopathic slow-transit constipation

Background: Some patients with Hirschsprung's disease have refractory const ipation following excision of aganglionic bowel, as do patients with idiopa thic slow-transit constipation (STC). Gut motility depends on enteric neuro nal development in response to expression of trophic factors and their rece ptors. Recent studies indicate the importance of neurotrophin 3 (NT-3) and its high-affinity receptor tyrosine kinase C (trk C) in enteric neuronal de velopment. Methods: Blinded quantitative immunohistochemical analysis of colon from pa tients with Hirschsprung's disease (aganglionic, hypoganglionic and normoga nglionic) (n = 5), STC (n = 6) and appropriate age-matched control tissues (n = 5) was performed for NT-3 and trk C, Sural nerve morphometry and immun ostaining were undertaken in three patients with STC who had abnormalities on limb autonomic and sensory testing. Results: A significantly higher proportion of submucous plexus neurones was trk C immunoreactive in control infant than adult colon (mean(s.e.m.) 73(9 ) versus 16(3) per cent of the total; P < 0.001), in accord with a role in development. The proportion of submucous plexus trk C-immunoreactive neuron es was reduced in colon from patients with Hirschsprung's disease (28(7) pe r cent of total in normoganglionic Hirschsprung's disease; P<0.007 versus i nfant controls) and STC (10(1) per cent of total; P = 0.053 versus adult co ntrols). No abnormalities of STC sural nerves were detected by morphometry or immunostaining. Conclusion: Decreased trk C expression may reflect developmental abnormalit ies in Hirschsprung's disease and idiopathic STC. Trk C activation by NT-3 or drugs may provide novel treatments.