An Embryological inquiry into the Patho-physiology of the Hirschsprung's disease---Special Reference to the Neuro-entero-glial Signaling Mechanism

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Hirschsprung's disease is characterized by the absence of intramural ganglion cells in the distal gut, resulting in bowel obstruction shortly after birth. Recently, germline mutations of RET, GDNF, SOX10, NGF, P2X7 and NTN genes have been reported in Hirschsprung's disease. Mutational analysis of these genes and expressional analysis of them according to gestational age of the embryos were undergone in murine model with Hirschsprung's disease. After these studies, we investigated the central and peripheral nervous systems in a SOX10 mutation associated Hirschsprung's disease patient who presented persistent gut functional disorders even after definitive surgery. DNA sequences of all coding regions of the SOX10 gene (22q13) were determined using the direct DyeDeoxy Terminator Cycle method, and brain magnetic resonance images, nerve conduction velocities, and histopathology of the enteric nervous system were investigated for neurologic assessment. In this patient, DNA analysis revealed a heterozygous nucleotide deletion (778delG) in SOX10 exon 5, causing a frameshift at codon 260 and resulting in premature transcriptional termination at codon 285. Neurologic studies disclosed brain hypomyelination, peripheral dysmyelinating neuropathy, and enteric neuroglia deficiency, which exclusively implied systemic glial maldevelopment. In conclusion, these results suggest that the enteric nervous system in patients with SOX10-associated Hirschsprung's disease is entirely subject to neuroglial impairment. This may explain persistent gut motility and absorption insufficiency after pull-through surgery, especially in children with allelic SOX10 truncating mutations.