Genotypically defined lissencephalies show distinct pathologies
Genotypically defined lissencephalies show distinct pathologies
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DOI：
10.1097/01.jnen.0000182978.56612.41
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发表时间：
2005-10-01
影响因子：
3.2
通讯作者：
Golden, JA
中科院分区：
文献类型：
--
作者：
Forman, MS;Squier, W;Golden, JA
无脑畸形传统上分为两种不同的病理形式：经典型（1型）和鹅卵石型（11型）。迄今为止，4个基因（LIS 1、DCX、CRISN和ARX）的突变与不同的I型无脑畸形综合征相关。这些基因中的每一个已被证明在正常细胞迁移中发挥作用，与I型无脑畸形的假定发病机制一致。基于这些数据，我们假设所有类型的X线片定义的I型无脑回畸形，无论基因型如何，在病理学上都是相似的。为了验证这一假设，我们检查了16名患者的大脑，其中包括15名无脑患者和1名皮质下带状异位患者。在这16名患者中，6名患者有LIS缺失，2名患者有DCX突变，2名患者有ARX突变。此外，6例患者没有明确的遗传缺陷，尽管皮质下带状异位患者表现出与XLIS突变预期相同的畸形模式。在所有病例中，皮质增厚;然而，皮质病理学的地形分布各不相同，范围从额叶至枕叶偏向的病理学到新皮质的弥漫性受累。尽管具有LIS缺失的脑表现出经典的4层无脑结构，但具有DCX和ARX突变的患者各自具有不同于LIS的独特细胞结构发现。此外，5例无已知遗传缺陷的患者中有2例表现出第四种组织病理学类型，其特征在于2层皮质。有趣的是，第四类无脑回畸形的2个大脑显示出严重的脑干和小脑异常。总之，我们确定了至少4种不同的组织病理学亚型的无脑回，分层与潜在的遗传缺陷。基于这些数据，提出了一个新的无脑回畸形的分类，结合病理和遗传学的结果。
Lissencephaly is traditionally divided into 2 distinct pathologic forms: classic (type 1) and cobblestone (type 11). To date, mutations in 4 genes, LIS], DCX, RELN, and ARX, have been associated with distinct type I lissencephaly syndromes. Each of these genes has been shown to play a role in normal cell migration, consistent with the presumed pathogenesis of type I lissencephaly. Based on these data, we hypothesized that all forms of radiographically defined type I lissencephaly independent of genotype would be pathologically similar. To test this hypothesis, we examined brains from 16 patients, including 15 lissencephalic patients and one patient with subcortical band heterotopia. Of these 16 patients, 6 had LIS] deletions, 2 had DCX mutations, and 2 had ARX mutations. In addition, 6 patients had no defined genetic defect, although the patient with subcortical band heterotopia exhibited the same pattern of malformation expected with an XLIS mutation. In all cases, the cortex was thickened; however, the topographic distribution of the cortical pathology varied, ranging from frontal- to occipital-biased pathology to diffuse involvement of the neocortex. Although brains with LIS] deletions exhibited the classic 4-layer lissencephalic architecture, patients with DCX and ARX mutations each had unique cytoarchitectural findings distinct from LIS]. Furthermore, 2 of the 5 patients with no known genetic defect showed a fourth type of histopathology characterized by a 2-layered cortex. Interestingly, the 2 brains with the fourth type of lissencephaly showed profound brainstem and cerebellar abnormalities. In summary, we identified at least 4 distinct histopathologic subtypes of lissencephaly that stratify with the underlying genetic defect. Based on these data, a new classification for lissencephaly is proposed that incorporates both pathologic and genetic findings.