Yui Kunio, Imataka George, Sasaki Hitomi, Kawasaki Yohei, Yoshihara Shigemi
Department of Urology, Fujita Health University Hospital, Toyoake, JPN.
Department of Pediatrics, Dokkyo Medical University Hospital, Mibu, JPN.
Cureus. 2020 Feb 8;12(2):e6920. doi: 10.7759/cureus.6920.
Tuberous sclerosis complex (TSC) is a genetic disorder with a high prevalence of associated autism spectrum disorder (ASD). The pathophysiology of TSC mainly involves the hyperactivation of mammalian target of rapamycin (mTOR) induced by TSC1 (hamartin) and TSC2 (tuberin) heterozygosity. The mTOR inhibitor, everolimus, is a therapeutic target for TSC-related ASD. The efficacy of everolimus may be affected by iron and copper neurotransmission and oxidant-antioxidant systems. Creatine has an antioxidant activity related to the cytoprotective paradigm. Additionally, TSC-related epileptic activity may influence the development of autistic symptoms. This case series examined the efficacy of everolimus in relation to the serum levels of the iron mediator (transferrin (Tf)), the copper mediator (ceruloplasmin (Cp)), the oxidant marker (oxidized low-density lipoprotein (oxLDL)), the antioxidant marker (total antioxidant power (TAP)), and creatine in four cases of TSC accompanied with autism. Everolimus improved autistic symptoms with increased serum Cp and Tf levels in all four cases. Serum TAP and creatine levels showed positive correlations with decreased total Aberrant Behavior Checklist (ABC) and Social Responsiveness Scale (SRS) scores, respectively. As everolimus regulates iron homeostasis and increased copper levels suppress mTOR signaling, everolimus improved autism symptoms with increased serum levels of Cp and Tf via homeostatic control of mTOR activity, accompanied with the considerable overlap of oxidant-antioxidant systems, such as TAP and creatine. Everolimus had no effect on TSC-related epileptiform discharges; thus, the autistic symptoms and epileptic activity may be two independent end results of a common central nervous system including mTOR hyperactivity.
结节性硬化症（TSC）是一种遗传性疾病，伴有自闭症谱系障碍（ASD）的患病率很高。TSC的病理生理学主要涉及由TSC1（错构瘤蛋白）和TSC2（结节蛋白）杂合性诱导的雷帕霉素哺乳动物靶标（mTOR）的过度激活。mTOR抑制剂依维莫司是TSC相关ASD的治疗靶点。依维莫司的疗效可能受铁和铜神经传递以及氧化还原系统的影响。肌酸具有与细胞保护模式相关的抗氧化活性。此外，TSC相关的癫痫活动可能影响自闭症症状的发展。本病例系列研究了依维莫司对4例伴有自闭症的TSC患者血清中铁介质（转铁蛋白（Tf））、铜介质（铜蓝蛋白（Cp））、氧化应激标志物（氧化型低密度脂蛋白（oxLDL））、抗氧化标志物（总抗氧化能力（TAP））和肌酸水平的疗效。依维莫司改善了自闭症症状，所有4例患者的血清Cp和Tf水平均升高。血清TAP和肌酸水平分别与总异常行为检查表（ABC）和社会反应量表（SRS）评分降低呈正相关。由于依维莫司调节铁稳态，而铜水平升高抑制mTOR信号传导，依维莫司通过对mTOR活性的稳态控制提高血清Cp和Tf水平，从而改善自闭症症状，同时伴有氧化还原系统（如TAP和肌酸）的大量重叠。依维莫司对TSC相关的癫痫样放电没有影响；因此，自闭症症状和癫痫活动可能是包括mTOR过度活跃在内的常见中枢神经系统的两个独立终末结果。
