Congenital diseases of dysmotility are a serious problem in children and, potentially, also in adults. Advances have recently been made in understanding one cause of pediatric dysmotility, Hirschsprung’s disease, which is the most visible congenital defect of the enteric nervous system (ENS).1–5 Although the diagnosis of Hirschsprung’s disease is sometimes missed, and the length of involved gut may vary,6,7 a segment of bowel is always totally aganglionic in patients with Hirschsprung’s disease, which is about an unsubtle as a defect can be. The ENS, however, can be abnormal without being aganglionic. This is true because the function of the ENS is much more sophisticated than that of other regions of the autonomic nervous system.8 The output of the ENS is not a simple binary choice to drive motility or not, or to stimulate secretion or not. The ENS is responsible for the integrative control of behavior, a function that is sufficiently complex as to require all of the classes of neurotransmitter found in the CNS and at least as many neurons as are found in the spinal cord (~108 in humans).4,9–12 The ENS does not simply accept commands from the brain and spinal cord, it also talks back to the CNS. The transfer of information between the bowel and the brain in the vagus nerves is two-way process and in fact, many more vagal fibers are afferent than efferent.13 Vagus nerve stimulation can be employed to affect epilepsy,14–16 treat depression16–18 and even to improve learning and memory.19 To function normally, therefore, the ENS requires a full panoply of neurons of correct phenotypes, proper synaptic connections, and an appropriate interaction with the CNS. More is needed of development, therefore, than just to produce relay ganglia to enable the brain to drive the gut. Despite the progress made in comprehending the aganglionosis of Hirschsprung’s disease, little is known about subtle abnormalities in subsets of enteric neurons, ENS synapses, or in the establishment of CNS-ENS interactions. Aganglionosis of the type seen in Hirschsprung’s disease cannot be the cause of functional bowel diseases, which are not lethal and are not associated with pseudoobstruction. If there is a developmental defect that causes functional bowel diseases, that defect has to be compatible with propulsive motility because propulsive motility occurs in patients with functional bowel diseases, even if the propulsive motility is so abnormal that the patient is driven to distraction. Abdominal distress from a bowel that propels may be particularly troublesome in children who may not be able to find a constructive means of conveying their difficulty. A congenital defect in the ENS that causes motility to be abnormal but present is likely to be one that affects committed sublineages of neural or glial precursors rather than pluripotent stem cells and thus to occur relatively late in ENS ontogeny.20 Such a late-arising, seemingly limited defect could also stop propulsive motility if it were to disrupt the function of a critical cell, such as the intrinsic primary afferent neurons (IPANs) that are required for the gut to be able to respond to luminal stimuli.21–25 Motility may then be compromised severely even when the pathology of the ENS, examined with conventional stains, is described as normal. This type of defect may be responsible for the still-to-be explained pediatric dysmotilities and chronic intestinal pseudoobstruction (CIP). This review is designed to examine the development of the ENS, not as a detailed catalogue of all known relevant phenomena, but to provide a conceptual basis for understanding, not only the pathogenesis of Hirschsprung’s disease, but also other disorders of dysmotility that are not associated with aganglionosis. Emphasis will be placed on genes that, when mutated, give rise to defects in the ENS that are not obvious but which nevertheless cause intestinal motility to become subtly or devastatingly abnormal.
Read full abstract
May 1, 2020
Letizia Zenzeri + 5
Open Access