Contribution of Transferrin and Ceruloplasmin Neurotransmission and Oxidant/Antioxidant Status to the Effects of Everolimus: A Case Series.

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.