Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, 75013 Paris, France; APHP Sorbonne Université, GH Pitié Salpêtrière et Trousseau, Département de Génétique, Centre de référence "déficiences intellectuelles de causes rares", Paris, France.
Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, 75013 Paris, France.
Neurobiol Dis. 2023 Jun 15;182:106144. doi: 10.1016/j.nbd.2023.106144. Epub 2023 May 4.
The mechanistic target of rapamycin (mTOR) signaling pathway is an essential regulator of numerous cellular activities such as metabolism, growth, proliferation, and survival. The mTOR cascade recently emerged as a critical player in the pathogenesis of focal epilepsies and cortical malformations. The 'mTORopathies' comprise a spectrum of cortical malformations that range from whole brain (megalencephaly) and hemispheric (hemimegalencephaly) abnormalities to focal abnormalities, such as focal cortical dysplasia type II (FCDII), which manifest with drug-resistant epilepsies. The spectrum of cortical dysplasia results from somatic brain mutations in the mTOR pathway activators AKT3, MTOR, PIK3CA, and RHEB and from germline and somatic mutations in mTOR pathway repressors, DEPDC5, NPRL2, NPRL3, TSC1 and TSC2. The mTORopathies are characterized by excessive mTOR pathway activation, leading to a broad range of structural and functional impairments. Here, we provide a comprehensive literature review of somatic mTOR-activating mutations linked to epilepsy and cortical malformations in 292 patients and discuss the perspectives of targeted therapeutics for personalized medicine.
雷帕霉素靶蛋白（mTOR）信号通路是调节细胞代谢、生长、增殖和存活等多种细胞活动的关键分子。mTOR 级联反应最近被认为是局灶性癫痫和皮质发育不良等疾病的重要发病机制之一。“mTOR 病”是一组皮质发育不良疾病，包括全脑（巨脑畸形）和半球（巨脑回畸形）异常，以及局灶性异常，如局灶性皮质发育不良 II 型（FCDII），这些疾病表现为耐药性癫痫。皮质发育不良的发生是由于 mTOR 通路激活剂 AKT3、MTOR、PIK3CA 和 RHEB 的体细胞突变，以及 mTOR 通路抑制剂 DEPDC5、NPRL2、NPRL3、TSC1 和 TSC2 的种系和体细胞突变所致。mTOR 病的特征是 mTOR 通路过度激活，导致广泛的结构和功能损伤。在这里，我们对 292 例与癫痫和皮质发育不良相关的 mTOR 激活体细胞突变进行了全面的文献回顾，并讨论了靶向治疗在个体化医学中的应用前景。
