Crino P B, Henske E P
Department of Neurology, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
Neurology. 1999 Oct 22;53(7):1384-90. doi: 10.1212/wnl.53.7.1384.
To outline recent developments in the neurobiology of the tuberous sclerosis complex (TSC).
TSC may be associated with neuropsychiatric disorders including epilepsy, mental retardation, and autism. The uncontrolled growth of subependymal giant cell astrocytomas may lead to hydrocephalus and death. The recent identification of mutations in two genes (TSC1 and TSC2) that cause TSC has led to rapid progress in understanding the molecular and cellular pathogenesis of this disorder. How distinct mutations lead to the varied clinical phenotype of TSC is under intense investigation.
We report the recent diagnostic criteria for TSC and provide an overview of the molecular genetics, molecular pathophysiology, and neuropathology of TSC. Important diagnostic criteria for TSC include facial angiofibromas, ungual fibromas, retinal hamartomas, and cortical tubers. Both familial and sporadic TSC cases occur. Approximately 50% of TSC families show genetic linkage to TSC1 and 50% to TSC2. Among sporadic TSC cases, mutations in TSC2 are more frequent and often accompanied by more severe neurologic deficits. Multiple mutational subtypes have been identified in the TSC1 and TSC2 genes. The TSC1 (chromosome 9) and TSC2 (chromosome 16) genes encode distinct proteins, hamartin and tuberin, respectively, which are widely expressed in the brain and may interact as part of a cascade pathway that modulates cellular differentiation, tumor suppression, and intracellular signaling. Tuberin has a GTPase activating protein-related domain that may contribute to a role in cell cycle passage and intracellular vesicular trafficking.
Identification of tuberous sclerosis complex (TSC) gene mutations has fostered understanding of how brain lesions in TSC are formed. Further characterization of the roles of hamartin and tuberin will provide potential therapeutic avenues to treat seizures, mental retardation, and tumor growth in TSC.
概述结节性硬化症（TSC）神经生物学的最新进展。
TSC可能与神经精神疾病有关，包括癫痫、智力迟钝和自闭症。室管膜下巨细胞星形细胞瘤的不受控制生长可能导致脑积水和死亡。最近发现导致TSC的两个基因（TSC1和TSC2）发生突变，这在理解该疾病的分子和细胞发病机制方面取得了快速进展。不同的突变如何导致TSC的不同临床表型正在深入研究中。
我们报告了TSC的最新诊断标准，并概述了TSC的分子遗传学、分子病理生理学和神经病理学。TSC的重要诊断标准包括面部血管纤维瘤、甲周纤维瘤、视网膜错构瘤和皮质结节。TSC既有家族性病例，也有散发性病例。大约50%的TSC家族显示与TSC1存在遗传连锁，50%与TSC2存在遗传连锁。在散发性TSC病例中，TSC2突变更常见，且常伴有更严重的神经功能缺陷。在TSC1和TSC2基因中已鉴定出多种突变亚型。TSC1（9号染色体）和TSC2（16号染色体）基因分别编码不同的蛋白质，即错构瘤蛋白和结节蛋白，它们在大脑中广泛表达，可能作为调节细胞分化、肿瘤抑制和细胞内信号传导的级联途径的一部分相互作用。结节蛋白有一个与GTP酶激活蛋白相关的结构域，可能在细胞周期进程和细胞内囊泡运输中发挥作用。
结节性硬化症（TSC）基因突变的鉴定促进了对TSC脑损伤形成方式的理解。对错构瘤蛋白和结节蛋白作用的进一步表征将为治疗TSC中的癫痫、智力迟钝和肿瘤生长提供潜在的治疗途径。
