Pathogenesis and epileptogenicity in tuberous sclerosis and focal cortical dysplasia

两种类型的致痫灶，结节性硬化症（TS）皮质结节和局灶性皮质发育不良（FCD）病变，表现出相似的组织病理学表现。我们利用手术或尸检获得的脑组织材料，比较了TS和FCD的免疫病理特征。首先，免疫组织化学研究了TS基因的蛋白产物，错构体和tuberin的表达。在TS皮质管中，这些蛋白在正常大小的神经元和胶质细胞中免疫反应性较弱，在异常巨细胞中免疫反应性中等。在FCD病变中，正常大小细胞的免疫反应性与对照组织相当，许多异常巨细胞对tuberin呈强烈阳性。接下来，我们研究了调节神经元迁移的蛋白双皮质素和fukutin的表达。部分异常巨细胞表现出这些胎儿蛋白的超期表达，其数量在TS组高于FCD组。然而，表达水平在患者、病变和细胞之间变化很大，仅根据免疫组织化学结果无法明确区分TS和FCD。许多与ts相关的肾脏和心脏肿瘤是由TSC1或TSC2基因杂合性缺失（LOH）引起的。相比之下，以往的研究未能在大多数皮质块茎中检测到LOH。利用TS动物模型Eker大鼠皮质管，通过显微解剖和巢式PCR检测单个巨细胞神经元的Tsc2基因状态。结果显示，巨细胞神经元中LOH缺失，说明皮质结节的发病机制不同于ts相关肿瘤。

Two types of epileptogenic foci, cortical tubers of tuberous sclerosis (TS) and lesions of focal cortical dysplasia (FCD), show similar histopathologic findings. Using cerebral tissue materials obtained by surgery or necropsy, we compared the immunopathologic features of TS and FCD. First, the expression of protein products of the genes responsible for TS, hamartin and tuberin, was studied immunohistochemically. In the cortical tubers of TS, immunoreactivities for these proteins were weak in normal sized neurons and glial cells, and moderate in abnormal giant cells. In the FCD lesions, immunoreactivities of normal sized cells were comparable to control tissues, and many abnormal giant cells were strongly positive for tuberin. Next, the expression of proteins regulating neuronal migration, doublecortin and fukutin, was studied. Some abnormal giant cells showed an overdue expression of these fetal proteins, the number of which was larger in TS than in FCD. However, the expression levels were highly variable among patients, lesions and cells, excluding clear distinction between TS and FCD based on immunohistochemical findings alone.Many of the TS-associated tumors in the kidneys and heart result from loss of heterozygosity (LOH) involving either the TSC1 or TSC2 gene. By contrast, previous studies have failed to detect LOH in most cortical tubers. Using a cortical tuber of the Eker rat, an animal model of TS, we examined the Tsc2 gene status of individual cytomegalic neurons, by microdissection and nested PCR. The results indicated the absence of LOH in the cytomegalic neurons, demonstrating that the pathogenesis of corticaltubers is different from that of TS-associated tumors.