Induction Mechanism of Apoptosis in Cerebrotendinous Xanthomatosis

CTX通常在青少年早期发病，在这个阶段最常观察到智力迟钝。锥体征和进行性小脑症状出现于青春期，伴发步态不整、侧眼震颤或言语障碍。青少年白内障也出现在青少年后期。最具特征性的症状是脑、肌腱、肌肉和肺的黄色瘤。对症治疗，口服鹅去氧胆酸可有效缩小瘤体。通过喂养实验，证实高浓度胆甾烷醇可引起小脑胆甾烷醇蓄积，并引起神经功能障碍。我们提出了一个假设，CTX患者血清中的胆甾烷醇可能会导致小脑神经元细胞死亡，最终发生小脑共济失调。本研究通过建立高胆固醇血症大鼠模型，观察了胆固醇对小脑神经细胞、角膜内皮细胞和透镜上皮细胞死亡的影响 ...更多信息 电池。在这些细胞中，胆甾烷醇培养的细胞凋亡是明显的。由于白细胞介素-1 β-转化酶（ICE）和CPP 32蛋白酶的活性在胆甾烷醇培养的细胞中增加，所有这些数据综合起来表明胆甾烷醇诱导细胞凋亡。这一结果可能解释了CTX患者小脑共济失调、白内障和角膜混浊的发生机制。我们研究了一位44岁的女性，患有进行性额叶痴呆和痉挛性截瘫。血清胆固醇水平升高，胆固醇27-羟化酶基因（CYP 27）发生杂合突变，基因组441位密码子同时存在G和A，提示CGG 441 Arg突变为CAG 441 Gln的杂合突变。脑计算机断层扫描和磁共振成像（MRI）显示大脑萎缩，在额叶区域明显。脑MR图像显示视放射侧脑室的白色物质中弥漫对称的高信号区。少

Onset of CTX is usually in early teens and mental retardation is most frequently observed at this stage. Pyramidal sign and progressive cerebellar symptom appear at puberty together with atactic gait, lateral nystagmus or atactic dysphasia. Juvenile cataract also appears in late teens. Most characteristic symptom is xanthoma in brain, tendon, muscle and lung. Treatment is symptomatic therapy, and oral administration of chenodeoxycholic acid is effective to reduce the size of xan-thoma. By feeding experiments, we proved that the high concentration of cholestanol induced the accumulation of chole-stanol in cerebellum and caused the neurological disturbance. We formulated a hypothesis that cholestanol in serum of CTX patients might induce neuronal cell death in cerebellum and eventually cerebellar ataxia would occur. In the present study, we developed hypercholestanolemia rats and examined the effects of cholestanol on death of cerebellar neuronal cells, corneal endothelial and lens epith … More elial cells. Apoptosis was evident in cells cultured with cholestanol in these cells. As activities of interleukin-1β-converting enzyme (ICE) and CPP32 protease were increased in cells cultured with cholestanol, all these data taken together suggest that cholestanol induced apoptosis. Our observation may explain the mechanism of cerebellar ataxia, cataract and corneal opacities of CTX patients. We studied a 44-year old woman with progressive frontal lobe dementia and spastic araplegia. Examination revealed increased serum levels of cholestanol and heterozygous mutation of the sterol 27-hydroxylase gene (CYP27), In genomic DNA, both the G and A were found at codon 441, indicating the heterozygous pattern of the mutation of CGG441Arg to CAG441Gln. Computed tomography and magnetic resonance imaging (MRI) of the brain showed cerebral atrophy, which was marked in the frontal area. Cerebral MR images showed diffuse symmetric areas of hyperintensity in the white matter of the lateral ventricles in the optic radiation. Less