Genotype/Phenotype Correlations in Tuberous Sclerosis Complex

Paolo Curatolo MD, Romina Moavero MD, Denis Roberto, Federica Graziola Seminars in Pediatric Neurology Volume 22, Issue 4, December 2015, Pages 259–273

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of widespread hamartomatous lesions in various organs, including brain, skin, kidneys, heart, and eyes. Central nervous system is almost invariably involved, with up to 85% of patients presenting with epilepsy, and at least half of patients having intellectual disability or other neuropsychiatric disorders including autism spectrum disorder. TSC is caused by the mutation in one of the 2 genes TSC1, at 9q34, and TSC2, at 16p13.3. They respectively encode for hamartin and tuberin, which form an intracellular complex inhibiting the mammalian target of rapamycin. Mammalian target of rapamycin overactivation following the genetic defect determines the cell growth and proliferation responsible for TSC-related lesions, as well as the alterations in neuronal excitability and synaptogenesis leading to epilepsy and neuropsychiatric disorders. A causative mutation for the disorder is identified in about 85% of patients with a clinical diagnosis of TSC. Mosaicism and technology limits likely explain most of the no mutation identified cases. This review confirms that patients with TSC2 mutations considered as a group usually present a more severe phenotype, characterized by higher number of tubers, earlier age at seizure onset and higher prevalence of intellectual disability. However, the clinical phenotype of the disease presents a high variability, thus making the prediction of the phenotype on an individual basis still challenging. The increasing application of new molecular techniques to subjects with TSC has the potential to significantly reduce the rate of patients with no mutation demonstrated and to identify an increasing higher number of mutations. This would hopefully allow a better characterization of higher risk mutations, which might help clinicians to plan individualized surveillance plans. Furthermore, the increasing availability of disease registries to collect clinical and genetics data of patients help to define more valid and clinically oriented genotype or phenotype correlations.

中文翻译：

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TSC 中更新的基因型-表型相关性

结节性硬化症基因型/表型相关性

Paolo Curatolo MD、Romina Moavero MD、Denis Roberto、Federica Graziola 小儿神经病学研讨会第 22 卷，第 4 期，2015 年 12 月，第 259–273 页

结节性硬化症 (TSC) 是一种常染色体显性遗传疾病，其特征是在多个器官（包括脑、皮肤、肾脏、心脏和眼睛）中出现广泛的错构瘤病变。中枢神经系统几乎无一例外地受到影响，高达 85% 的患者出现癫痫，至少一半的患者患有智力障碍或其他神经精神疾病，包括自闭症谱系障碍。TSC 是由 9q34 处的 2 个基因 TSC1 和 16p13.3 处的 TSC2 之一的突变引起的。它们分别编码错构蛋白和马铃薯蛋白，形成细胞内复合物抑制雷帕霉素的哺乳动物靶点。遗传缺陷后的哺乳动物雷帕霉素靶标过度激活决定了导致 TSC 相关病变的细胞生长和增殖，以及导致癫痫和神经精神疾病的神经元兴奋性和突触发生的改变。约 85% 临床诊断为 TSC 的患者中发现了该疾病的致病突变。镶嵌现象和技术限制可能解释了大多数未发现突变的病例。本综述证实，具有 TSC2 突变的患者作为一个群体通常表现出更严重的表型，其特征是结节数量较多、癫痫发作年龄较早以及智力障碍患病率较高。然而，该疾病的临床表型呈现出很高的变异性，因此对个体表型的预测仍然具有挑战性。新的分子技术越来越多地应用于 TSC 受试者，有可能显着降低未显示突变的患者比例，并识别出越来越多的突变。这有望更好地描述高风险突变，这可能有助于临床医生规划个性化的监测计划。此外，越来越多的疾病登记处可以收集患者的临床和遗传学数据，这有助于定义更有效和面向临床的基因型或表型相关性。