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）的皮质结节和局灶性皮质发育不良（FCD）的病变，表现出相似的组织病理学结果。利用手术或尸检获得的脑组织材料，我们比较了TS和FCD的免疫病理学特征。首先，化学方法研究了TS基因的蛋白质产物，即hamartin和tuberin的表达。在皮质块茎的TS，这些蛋白的免疫反应性弱，在正常大小的神经元和胶质细胞，和中度异常巨细胞。在FCD病变中，正常大小细胞的免疫反应性与对照组织相当，许多异常巨细胞对结核菌素呈强阳性。接下来，研究了调节神经元迁移的蛋白质doublecortin和fukarin的表达。一些异常的巨细胞表现出这些胎儿蛋白的逾期表达，其数量在TS比FCD更大。然而，表达水平在患者、病变和细胞之间高度可变，不包括仅基于免疫组化结果的TS和FCD之间的明确区别。许多肾脏和心脏中的TS相关肿瘤是由涉及TSC 1或TSC 2基因的杂合性缺失（洛）引起的。相比之下，以前的研究未能在大多数皮质结节中检测到洛缺失。使用皮质结节的Eker大鼠，TS的动物模型，我们研究了个别巨细胞神经元的Tsc 2基因状态，通过显微切割和巢式PCR。结果表明，在巨细胞神经元中没有洛缺失，表明皮质结节的发病机制与TS相关肿瘤不同。

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.