PMID- 25591831
OWN - NLM
STAT- MEDLINE
DCOM- 20151112
LR  - 20211203
IS  - 1873-5150 (Electronic)
IS  - 0887-8994 (Linking)
VI  - 52
IP  - 3
DP  - 2015 Mar
TI  - Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated 
      epilepsy.
PG  - 281-9
LID - S0887-8994(14)00659-6 [pii]
LID - 10.1016/j.pediatrneurol.2014.10.028 [doi]
AB  - BACKGROUND: Tuberous sclerosis complex is a multiorgan disease resulting from a 
      mutation of one of two TSC genes. The two gene products form a functional complex 
      that regulates the mTOR signaling pathway (mTOR initially represented mammalian 
      target of rapamycin, but increasingly the term mechanistic target of rapamycin is 
      used to reflect the ubiquitous occurrence of mTOR). Epilepsy is the most common 
      neurological symptom of tuberous sclerosis complex, occurring in 80% to 90% of 
      affected individuals over the course of their lifetimes and causing significant 
      morbidity and mortality. The mechanistic target of rapamycin (mTOR) signaling 
      pathway is intricately involved in multiple cellular functions--including protein 
      synthesis, cell growth and proliferation, and synaptic plasticity--which may 
      influence neuronal excitability and precipitate epileptogenesis. Recent 
      preclinical and clinical studies have increased interest in the potential role of 
      mTOR inhibitors for the treatment of tuberous sclerosis complex-related epilepsy. 
      METHODS: Medline and PubMed database searches were used to identify relevant 
      studies and other information on tuberous sclerosis complex-related epilepsies, 
      the mTOR pathway, and current advances in treatment approaches. RESULTS: Although 
      current management strategies that provide symptomatic relief are effective at 
      reducing the frequency of seizures in individuals with tuberous sclerosis 
      complex, there is further room for the exploration of therapies that directly 
      address hyperactive mTOR signaling--the underlying etiology of the disease. The 
      role of the antiepileptic effect of mTOR inhibition was first demonstrated in 
      knockout TSC1 mouse models. Additionally, several case studies demonstrated a 
      positive effect on seizure frequency and severity in patients with 
      pharmacoresistant epilepsy. In a phase 1/2 clinical trial with 28 patients, 
      clinically relevant reduction in overall seizure frequency was documented in 
      individuals treated with the mTOR inhibitor everolimus. In a phase 3 trial 
      evaluating the role of everolimus in subependymal giant cell astrocytoma, 
      seizures were a secondary end point. Because the median seizure frequency was 
      zero in this study, the analysis was inconclusive. CONCLUSION: Various 
      preclinical models provide substantial evidence for the role of mTOR inhibition 
      in the treatment of epilepsy in individuals with tuberous sclerosis complex. 
      Preliminary clinical studies provide supportive evidence for a role of mTOR 
      inhibition in the management of tuberous sclerosis complex-associated epilepsy 
      and pave the way for new randomized placebo-controlled studies. This article 
      reviews current treatment recommendations for the management of tuberous 
      sclerosis complex-associated epilepsy as well as the rationale and evidence to 
      support the use of mTOR inhibitors.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Curatolo, Paolo
AU  - Curatolo P
AD  - Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata 
      University of Rome, Rome, Italy. Electronic address: curatolo@uniroma2.it.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20141120
PL  - United States
TA  - Pediatr Neurol
JT  - Pediatric neurology
JID - 8508183
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (TESC protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Calcium-Binding Proteins/genetics
MH  - Drug Evaluation, Preclinical
MH  - Epilepsy/*drug therapy/*etiology
MH  - Humans
MH  - Immunosuppressive Agents/*therapeutic use
MH  - Sirolimus/*therapeutic use
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Tuberous Sclerosis/*complications/genetics
OTO - NOTNLM
OT  - epilepsy
OT  - epileptogenesis
OT  - mTOR inhibitor
OT  - mammalian target of rapamycin
OT  - mechanistic target of rapamycin
OT  - tuberous sclerosis complex
EDAT- 2015/01/17 06:00
MHDA- 2015/11/13 06:00
CRDT- 2015/01/17 06:00
PHST- 2014/07/10 00:00 [received]
PHST- 2014/09/29 00:00 [revised]
PHST- 2014/10/29 00:00 [accepted]
PHST- 2015/01/17 06:00 [entrez]
PHST- 2015/01/17 06:00 [pubmed]
PHST- 2015/11/13 06:00 [medline]
AID - S0887-8994(14)00659-6 [pii]
AID - 10.1016/j.pediatrneurol.2014.10.028 [doi]
PST - ppublish
SO  - Pediatr Neurol. 2015 Mar;52(3):281-9. doi: 10.1016/j.pediatrneurol.2014.10.028. 
      Epub 2014 Nov 20.