The treatment of tuberous sclerosis complex (TSC) using mammalian target of rapamycin (mTOR) inhibitors is clinically promising. The aim of the present study was to evaluate the efficacy and safety of mTOR inhibitors for improving the clinical symptoms of TSC. We performed a systematic search of major electronic databases (PubMed, EMBASE, Cochrane Library and WanFang, CNKI, and VIP databases) to identify randomized controlled trials (RCTs) and quasi-randomized studies from the date of database inception to November 2017; the Chinese Food and Drug Administration and clinicaltrials.gov were also searched for unpublished studies. The endpoints of the study were the tumor response rate and seizure frequency response rate (the proportion of patients achieving a ≥ 50% reduction relative to the baseline). Two researchers screened articles, assessed the risk of bias and extracted data independently. The included RCTs were analyzed using RevMan 5.3, which was provided by the Cochrane Collaboration. Compared with the placebo, mTOR inhibitors significantly reduced tumor volume in both angiomyolipoma (AML) (RR = 24.69, 95% CI = 3.51,173.41, P = 0.001) and subependymal giant cell astrocytoma (SEGA) (RR = 27.85, 95% CI = 1.74,444.82, P = 0.02). Compared with the placebo, mTOR inhibitors significantly reduced seizure frequency (RR = 2.12, 95% CI = 1.41,3.19, P = 0.0003). Regarding safety, compared with patients who did not receive mTOR inhibitors, those who did had a higher risk of suffering stomatitis (RR = 3.20, 95% CI = 1.49,6.86, P = 0.003). In contrast, patients who did and did not receive mTOR inhibitors experienced similar adverse events, such as upper respiratory tract infections (RR = 1.08, 95% CI = 0.81,1.45, P = 0.59) and nasopharyngitis (RR = 0.86, 95% CI = 0.60,1.21, P = 0.38). In view of the efficacy and safety associated with tumor and seizure frequency in the TSC patients, mTOR inhibitors is a good therapeutic choice. Unlike the risks of upper respiratory tract infections and nasopharyngitis, mTOR inhibitors seem to increase the risk of stomatitis, mostly grade 1 and 2.

Subtelomeric imbalance is widely accepted as related to developmental delay/mental retardation (DD/MR). Fine mapping of aberrations in gene-enriched subtelomeric regions provides essential clues for localizing critical regions, and provides a strategy for identifying new candidate genes. To date, no large-scale study has been conducted on subtelomeric aberrations in DD/MR patients in mainland China.

We attempted to determine whether the inflammatory pathway HMGB1-TLR4 and the downstream pro-inflammatory cytokines is upregulated in focal cortical dysplasia (FCD) type II and whether there is a correlation between the TLR4 upregulation and disease duration or frequency of epileptic seizures. FCD type II and peri-FCD paired tissues resected from eight children with refractory epilepsy were collected. Through real-time qPCR, Western blot, and co-immunoprecipitation, we examined the differences between FCD lesions and peri-FCD tissues with respect to mRNA expression, protein expression, and protein interaction in HMGB1-TLR4 pathway biomarker and downstream pro-inflammatory factors in whole brain tissue. Then, we used immunofluorescence to examine the difference between FCD lesions and peri-FCD tissues with respect to protein expression and intracellular distribution of HMGB1-TLR4 pathway biomarker in neurons, astrocytes, and oligodendrocytes. Correlation between level of TLR4 expression and disease duration or frequency of epileptic seizures in patients was also analyzed. The protein expression levels of TLR4, cytoplasm HMGB1, TLR4/MyD88 complex, ubiquitination of TRAF6, p-IKK, p-IκB-α, p-NF-κB p65, and IL-1β and TNF-α in lesion tissues were significantly higher than those in peri-FCD controls. Total mRNA expression levels of TLR4, IL-1β, and TNF-α in lesion tissues were significantly higher than those in peri-FCD controls, but HMGB1 had no significant change. In neurons and astrocytes inside the lesions, the expression of TLR4 protein was significantly higher than that in peri-FCD tissues, and HMGB1 was mainly expressed in the cytoplasm, while expressed in the nuclei in peri-FCD tissues. But in oligodendrocytes, there was no upregulation of HMGB1-TLR4 pathway in both lesions and peri-FCD tissues. We did not identify the correlation between the level of TLR4 activation and disease duration or frequency of epileptic seizures. The HMGB1-TLR4 pathway was upregulated in the neurons and astrocytes inside FCD type II lesions, which led to an increase in the release of downstream pro-inflammatory cytokines. Correlation between the level of TLR4 activation and duration or frequency of epileptic seizures was not identified.