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

先天性巨结肠疾病的特点是远端肠道内神经节细胞缺失，导致出生后不久肠梗阻。近年来，RET、GDNF、SOX10、NGF、P2X7和NTN基因的种系突变在巨结肠病中有报道。在巨结肠病小鼠模型中对这些基因进行了突变分析，并根据胚胎胎龄对其进行了表达分析。在这些研究之后，我们研究了一名SOX10突变相关的巨结肠病患者的中枢和周围神经系统，该患者即使在最终手术后仍出现持续的肠道功能障碍。采用直接染料脱氧终止循环法测定SOX10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组织病理学进行神经学评估。在该患者中，DNA分析显示SOX10外显子5杂合核苷酸缺失（778delG），导致密码子260处移码，导致密码子285处转录过早终止。神经学研究揭示了脑髓鞘退化、周围髓鞘异常神经病和肠内神经胶质缺乏，这完全暗示了系统性神经胶质发育不良。总之，这些结果表明，sox10相关巨结肠病患者的肠神经系统完全受神经胶质损伤的影响。这可能解释了拉通手术后持续的肠道蠕动和吸收不足，特别是在SOX10等位基因截断突变的儿童中。

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.