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

Abstract

Background: Some Patients With Hirschsprung's Disease Have Refractory Constipation Following Excision Of Aganglionic Bowel, As Do Patients With Idiopathic Slow-Transit Constipation (Stc). Gut Motility Depends On Enteric Neuronal Development In Response To Expression Of Trophic Factors And Their Receptors. Recent Studies Indicate The Importance Of Neurotrophin 3 (Nt-3) And Its High-Affinity Receptor Tyrosine Kinase C (Trk C) In Enteric Neuronal Development. Methods: Blinded Quantitative Immunohistochemical Analysis Of Colon From Patients With Hirschsprung's Disease (Aganglionic, Hypoganglionic And Normoganglionic) (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 Immunostaining 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 Neurones Was Reduced In Colon From Patients With Hirschsprung's Disease (28(7) Per Cent Of Total In Normoganglionic Hirschsprung's Disease; P < 0.007 Versus Infant Controls) And Stc (10(1) Per Cent Of Total; P = 0.053 Versus Adult Controls). No Abnormalities Of Stc Sural Nerves Were Detected By Morphometry Or Immunostaining. Conclusion: Decreased Trk C Expression May Reflect Developmental Abnormalities In Hirschsprung's Disease And Idiopathic Stc. Trk C Activation By Nt-3 Or Drugs May Provide Novel Treatments.