Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor gene syndrome due to germline mutations in either TSC1 or TSC2. 10-15% of TSC individuals have no mutation identified (NMI) ...after thorough conventional molecular diagnostic assessment. 53 TSC subjects who were NMI were studied using next generation sequencing to search for mutations in these genes. Blood/saliva DNA including parental samples were available from all subjects, and skin tumor biopsy DNA was available from six subjects. We identified mutations in 45 of 53 subjects (85%). Mosaicism was observed in the majority (26 of 45, 58%), and intronic mutations were also unusually common, seen in 18 of 45 subjects (40%). Seventeen (38%) mutations were seen at an allele frequency < 5%, five at an allele frequency < 1%, and two were identified in skin tumor biopsies only, and were not seen at appreciable frequency in blood or saliva DNA. These findings illuminate the extent of mosaicism in TSC, indicate the importance of full gene coverage and next generation sequencing for mutation detection, show that analysis of TSC-related tumors can increase the mutation detection rate, indicate that it is not likely that a third TSC gene exists, and enable provision of genetic counseling to the substantial population of TSC individuals who are currently NMI.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used for various benign tumours associated with tuberous sclerosis complex. We assessed the efficacy and ...safety of two trough exposure concentrations of everolimus, 3–7 ng/mL (low exposure) and 9–15 ng/mL (high exposure), compared with placebo as adjunctive therapy for treatment-resistant focal-onset seizures in tuberous sclerosis complex. Methods In this phase 3, randomised, double-blind, placebo-controlled study, eligible patients aged 2–65 years with tuberous sclerosis complex and treatment-resistant seizures (≥16 in an 8-week baseline phase) receiving one to three concomitant antiepileptic drugs were recruited from 99 centres across 25 countries. Participants were randomly assigned (1:1:1), via permuted-block randomisation (block size of six) implemented by Interactive Response Technology software, to receive placebo, low-exposure everolimus, or high-exposure everolimus. Randomisation was stratified by age subgroup (<6 years, 6 to <12 years, 12 to <18 years, and ≥18 years). Patients, investigators, site personnel, and the sponsor's study team were masked to treatment allocation. The starting dose of everolimus depended on age, body-surface area, and concomitant use of cytochrome 3A4/P-glycoprotein inducers. Dose adjustments were done to attain target trough ranges during a 6-week titration period, and as needed during a 12-week maintenance period of core phase. Patients or their caregivers recorded events in a seizure diary throughout the study. The primary endpoint was change from baseline in the frequency of seizures during the maintenance period, defined as response rate (the proportion of patients achieving ≥50% reduction in seizure frequency) and median percentage reduction in seizure frequency, in all randomised patients. This study is registered with ClinicalTrials.gov , number NCT01713946. Findings Between July 3, 2013, and May 29, 2015, 366 patients were enrolled and randomly assigned to placebo (n=119), low-exposure everolimus, (n=117), or high-exposure everolimus (n=130). The response rate was 15·1% with placebo (95% CI 9·2–22·8; 18 patients) compared with 28·2% for low-exposure everolimus (95% CI 20·3–37·3; 33 patients; p=0·0077) and 40·0% for high-exposure everolimus (95% CI 31·5–49·0; 52 patients; p<0·0001). The median percentage reduction in seizure frequency was 14·9% (95% CI 0·1–21·7) with placebo versus 29·3% with low-exposure everolimus (95% CI 18·8–41·9; p=0·0028) and 39·6% with high-exposure everolimus (95% CI 35·0–48·7; p<0·0001). Grade 3 or 4 adverse events occurred in 13 (11%) patients in the placebo group, 21 (18%) in the low-exposure group, and 31 (24%) in the high-exposure group. Serious adverse events were reported in three (3%) patients who received placebo, 16 (14%) who received low-exposure everolimus, and 18 (14%) who received high-exposure everolimus. Adverse events led to treatment discontinuation in two (2%) patients in the placebo group versus six (5%) in the low-exposure group and four (3%) in the high-exposure group. Interpretation Adjunctive everolimus treatment significantly reduced seizure frequency with a tolerable safety profile compared with placebo in patients with tuberous sclerosis complex and treatment-resistant seizures. Funding Novartis Pharmaceuticals Corporation.
Abstract Background Tuberous sclerosis complex is an autosomal dominant disorder predisposing to the development of benign lesions in different body organs, mainly in the brain, kidney, liver, skin, ...heart, and lung. Subependymal giant cell astrocytomas are characteristic brain tumors that occur in 10% to 20% of tuberous sclerosis complex patients and are almost exclusively related to tuberous sclerosis complex. Subependymal giant cell astrocytomas usually grow slowly, but their progression ultimately leads to the occlusion of the foramen of Monro, with subsequent increased intracranial pressure and hydrocephalus, thus necessitating intervention. During recent years, secondary to improved understanding in the biological and genetic basis of tuberous sclerosis complex, mammalian target of rapamycin inhibitors have been shown to be effective in the treatment of subependymal giant cell astrocytomas, becoming an alternative therapeutic option to surgery. Methods In June 2012, an International Tuberous Sclerosis Complex Consensus Conference was convened, during which an expert panel revised the diagnostic criteria and considered treatment options for subependymal giant cell astrocytomas. This article summarizes the subpanel's recommendations regarding subependymal giant cell astrocytomas. Conclusions Mammalian target of rapamycin inhibitors have been shown to be an effective treatment of various aspects of tuberous sclerosis complex, including subependymal giant cell astrocytomas. Both mammalian target of rapamycin inhibitors and surgery have a role in the treatment of subependymal giant cell astrocytomas. Various subependymal giant cell astrocytoma–related conditions favor a certain treatment.
Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has demonstrated efficacy in treating subependymal giant cell astrocytomas (SEGAs) and other manifestations of tuberous sclerosis complex ...(TSC). However, long-term use of mTOR inhibitors might be necessary. This analysis explored long-term efficacy and safety of everolimus from the conclusion of the EXIST-1 study (NCT00789828).
EXIST-1 was an international, prospective, double-blind, placebo-controlled phase 3 trial examining everolimus in patients with new or growing TSC-related SEGA. After a double-blind core phase, all remaining patients could receive everolimus in a long-term, open-label extension. Everolimus was initiated at a dose (4.5 mg/m2/day) titrated to a target blood trough of 5-15 ng/mL. SEGA response rate (primary end point) was defined as the proportion of patients achieving confirmed ≥50% reduction in the sum volume of target SEGA lesions from baseline in the absence of worsening nontarget SEGA lesions, new target SEGA lesions, and new or worsening hydrocephalus. Of 111 patients (median age, 9.5 years) who received ≥1 dose of everolimus (median duration, 47.1 months), 57.7% (95% confidence interval CI, 47.9-67.0) achieved SEGA response. Of 41 patients with target renal angiomyolipomas at baseline, 30 (73.2%) achieved renal angiomyolipoma response. In 105 patients with ≥1 skin lesion at baseline, skin lesion response rate was 58.1%. Incidence of adverse events (AEs) was comparable with that of previous reports, and occurrence of emergent AEs generally decreased over time. The most common AEs (≥30% incidence) suspected to be treatment-related were stomatitis (43.2%) and mouth ulceration (32.4%).
Everolimus use led to sustained reduction in tumor volume, and new responses were observed for SEGA and renal angiomyolipoma from the blinded core phase of the study. These findings support the hypothesis that everolimus can safely reverse multisystem manifestations of TSC in a significant proportion of patients.
ClinicalTrials.gov NCT00789828.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
To analyze the cumulative efficacy and safety of everolimus in treating subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis complex (TSC) from an open‐label phase ...II study (NCT00411619). Updated data became available from the conclusion of the extension phase and are presented in this ≥5‐year analysis.
Methods
Patients aged ≥ 3 years with a definite diagnosis of TSC and increasing SEGA lesion size (≥2 magnetic resonance imaging scans) received everolimus starting at 3mg/m2/day (titrated to target blood trough levels of 5–15ng/ml). The primary efficacy endpoint was reduction from baseline in primary SEGA volume.
Results
As of the study completion date (January 28, 2014), 22 of 28 (78.6%) initially enrolled patients finished the study per protocol. Median (range) duration of exposure to everolimus was 67.8 (4.7–83.2) months; 12 (52.2%) and 14 (60.9%) of 23 patients experienced SEGA volume reductions of ≥50% and ≥30% relative to baseline, respectively, after 60 months of treatment. The proportion of patients experiencing daily seizures was reduced from 7 of 26 (26.9%) patients at baseline to 2 of 18 (11.1%) patients at month 60. Most commonly reported adverse events (AEs) were upper respiratory tract infection and stomatitis of mostly grade 1 or 2 severity. No patient discontinued treatment due to AEs. The frequency of emergence of most AEs decreased over the course of the study.
Interpretation
Everolimus continues to demonstrate a sustained effect on SEGA tumor reduction over ≥5 years of treatment. Everolimus remained well‐tolerated, and no new safety concerns were noted. Ann Neurol 2015;78:929–938
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder that can affect every organ of the body, most commonly the brain, kidneys, heart, and lungs. The TSC mutation results ...in abnormal cellular proliferation and differentiation, which are responsible for hamartomatous lesions that affect the brain, kidney, heart, and lungs. mTOR (mammalian target of rapamycin) is a protein kinase that regulates the abnormal cellular proliferation and differentiation. Consequently, mTOR inhibitors are being studied to treat the subependymal giant-cell astrocytomas and renal angiomyolipomas that are commonly seen with TSC. We describe here the case of a patient with significant regression of a cardiac rhabdomyoma after receiving everolimus, an mTOR inhibitor. This finding suggests a possible novel therapy for patients with clinically significant cardiac rhabdomyomas.
Patients with Tuberous Sclerosis Complex (TSC) show aberrant wiring of neuronal connections formed during development which may contribute to symptoms of TSC, such as intellectual disabilities, ...autism, and epilepsy. Yet models examining the molecular basis for axonal guidance defects in developing human neurons have not been developed. Here, we generate human induced pluripotent stem cell (hiPSC) lines from a patient with TSC and genetically engineer counterparts and isogenic controls. By differentiating hiPSCs, we show that control neurons respond to canonical guidance cues as predicted. Conversely, neurons with heterozygous loss of TSC2 exhibit reduced responses to several repulsive cues and defective axon guidance. While TSC2 is a known key negative regulator of MTOR-dependent protein synthesis, we find that TSC2 signaled through MTOR-independent RHOA in growth cones. Our results suggest that neural network connectivity defects in patients with TSC may result from defects in RHOA-mediated regulation of cytoskeletal dynamics during neuronal development.
Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder that affects multiple organ systems throughout the body. Dysregulation of the mammalian target of rapamycin (mTOR) ...pathway is implicated in the disease pathology, and evidence exists to support the use of mTOR inhibitors in treatment. The mTOR pathway has also been investigated as a potential treatment target for several other rare diseases. TSC research has highlighted the value of pursuing targeted therapies based on underlying molecular pathophysiology. One goal of current research is to identify the role of mTOR inhibition in neurologic and developmental disorders apart from TSC. There is also particular interest in the potential role of mTOR inhibitors in preventing seizures, neurodevelopmental disabilities, renal tumors, cutaneous tumors, and other manifestations typically seen in TSC. It is foreseeable that use of mTOR inhibition to prevent long-term morbidity in TSC will become mainstream therapeutic practice. This review will provide an overview of the relationship between the mTOR pathway and TSC disease pathology, summarize the clinical evidence supporting the use of mTOR inhibitors for treatment of the various manifestations of TSC, and discuss the potential therapeutic role of mTOR inhibitors in several rare diseases.
Drug-resistant epilepsy (DRE) is common in tuberous sclerosis complex (TSC). The role of stiripentol (STP) in seizure treatment in this population is not well understood. This study evaluates the ...efficacy and tolerability of STP in patients with TSC with DRE.
We performed a retrospective review of patients with TSC with DRE. Seizure frequencies at 1 month before (baseline) and 1, 3, 6, and 12 months after STP initiation were collected.
Of the 1492 patients, 13 received STP and the number of patients with ≥50% seizure reduction at 1, 3, 6, and 12 months was 6/13 (46.2%), 4/13 (30.8%), 8/13 (61.5%), and 6/13 (46.2%), respectively. Six patients (46.2%) had favorable outcomes with persistent seizure reduction through 12 months. Their mean (±S.D.) percentage of seizure reduction at 1, 3, 6, and 12 months was 68.1 (±22.0), 71.3 (±23.2), 75.7 (±23.5), and 75.7 (±23.5), respectively. One patient had worsening seizures throughout the STP course. Three patients did not have seizure reduction until after 6 months, and 2 had initial seizure reduction before worsening. Younger age (P value <0.001), early STP treatment (P value <0.001), higher doses (P value = 0.004), and higher baseline seizure frequency (P value = 0.01) were associated with favorable outcomes. Side effects were seen in 85% of our cohort.
About 46% of the patients had favorable outcomes. Younger age, early STP treatment, higher doses, and higher baseline seizure frequency were significantly associated with favorable outcomes.
Background Lymphangioleiomyomatosis (LAM) occurs in at least 40% of women with tuberous sclerosis complex (TSC), as diagnosed based on chest CT scan findings. Early identification may inform ...lifestyle choices and treatment decisions. Here we report LAM prevalence in a large TSC clinic and propose an approach to CT scan screening for LAM in women with TSC. Methods We retrospectively reviewed initial chest CT scans of all female patients with TSC aged ≥ 15 years seen at our center over a 12-year period. Each CT image slice was manually scored for the presence or absence of characteristic thin-walled cysts, and the diagnosis of LAM was made if the sum of the cysts on all slices exceeded three cysts. Results Of 133 female patients with TSC, 101 had chest CT scans available for review. Forty-eight (47.5%) met criteria for TSC-LAM on the initial CT scan. The risk of LAM was age dependent, rising by about 8% per year. The prevalence of LAM was 27% in subjects < 21 years of age and 81% in subjects > 40 years of age. Among asymptomatic subjects with LAM, 84% had cysts present in the single image at the level of the carina. Most subjects with LAM eventually developed pulmonary symptoms (63%), and 12.5% died from LAM. Conclusions These results suggest that most women with TSC ultimately develop cystic changes consistent with LAM and that most cases can be identified from a single CT imaging slice at the level of the carina. TSC-LAM was associated with appreciable morbidity and mortality in this referral population. An age-based approach using limited CT scanning methods may facilitate screening and subsequent treatment decisions with decreased radiation exposure in this at-risk population.
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