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

先天性巨结肠的特征是远端肠壁内神经节细胞缺失，导致出生后不久肠梗阻。最近，RET、GDNF、SOX 10、NGF、P2X7和NTN基因的生殖系突变在先天性巨结肠中被报道。在先天性巨结肠小鼠模型中进行这些基因的突变分析和它们在不同胎龄胚胎中的表达分析。在这些研究之后，我们研究了与SOX 10突变相关的先天性巨结肠患者的中枢和外周神经系统，该患者即使在最终手术后也表现出持续的肠道功能障碍。使用直接DyeDeoxy Terminator Cycle方法测定SOX 10基因（22q13）所有编码区的DNA序列，并研究脑磁共振图像、神经传导速度和肠神经系统的组织病理学，以进行神经学评估。在该患者中，DNA分析显示SOX 10外显子5中的杂合核苷酸缺失（778delG），导致密码子260处的移码，并导致密码子285处的过早转录终止。神经系统研究发现脑髓鞘形成不足，周围髓鞘形成障碍性神经病，肠神经胶质细胞缺乏，这完全意味着全身神经胶质发育不良。总之，这些结果表明，与SOX 10相关的先天性巨结肠患者的肠神经系统是完全受到神经胶质细胞的损害。这可能解释了拉通手术后持续的肠道动力和吸收不足，特别是在等位基因SOX 10截短突变的儿童中。

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.