Tuberous Sclerosis Research Articles

TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex

Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and lesions in multiple organs including lung (lymphangioleiomyomatosis) and kidney (angiomyolipoma and renal cell carcinoma). Previously, we found that TFEB is constitutively active in TSC. Here, we generated two mouse models of TSC in which kidney pathology is the primary phenotype. Knockout of TFEB rescues kidney pathology and overall survival, indicating that TFEB is the primary driver of renal disease in TSC. Importantly, increased mTORC1 activity in the TSC2 knockout kidneys is normalized by TFEB knockout. In TSC2-deficient cells, Rheb knockdown or Rapamycin treatment paradoxically increases TFEB phosphorylation at the mTORC1-sites and relocalizes TFEB from nucleus to cytoplasm. In mice, Rapamycin treatment normalizes lysosomal gene expression, similar to TFEB knockout, suggesting that Rapamycin’s benefit in TSC is TFEB-dependent. These results change the view of the mechanisms of mTORC1 hyperactivation in TSC and may lead to therapeutic avenues.

The association between computed tomography attenuation value of renal angiomyolipoma associated with tuberous sclerosis complex and response to everolimus.

The response to everolimus in patients with renal angiomyolipoma associated with tuberous sclerosis complex (TSC-RAML) varies among individuals. This study aims to identify potential factors associated with the response to everolimus. We retrospectively examined data encompassing age, gender, tumor size, computed tomography attenuation value (CT value), CT enhancement, and tumor reduction rate in patients with TSC-RAML undergoing everolimus in two previously registered clinical trials. A total of 33 participants (29.33 ± 6.63years old, 20 females) were included. The correlation analysis conducted separately for tumors located in the left and right kidneys revealed significant negative correlations (P < 0.05) between tumor reduction rate and age, as well as tumor size. While significant positive correlations (P < 0.05) were observed between tumor reduction rate and unenhanced CT value as well as CT enhancement. Nonetheless, based on multiple linear regression analysis, unenhanced CT value emerged as the sole-independent predictor of tumor reduction rate among age, gender, tumor size, unenhanced CT value and CT enhancement for both left (coefficient = 0.00319, P < 0.0001) and right kidneys (coefficient = 0.00315, P = 0.0104). Notable reductions were observed in unenhanced CT value (- 3.81 vs - 24.70HU, P < 0.0001) and CT enhancement (48.16 vs 33.56HU, P < 0.0001) following a 3-month administration of everolimus. The decline in both unenhanced CT value and tumor size predominantly occurred within the initial 3months, subsequently maintaining a relatively stable level throughout the treatment. The unenhanced CT value of TSC-RAML showed an independent correlation with the response to everolimus, suggesting its potential as a predictor of everolimus efficacy in patients with TSC-RAML.

Cannabidiol (Epidyolex®) for severe behavioral manifestations in patients with tuberous sclerosis complex, mucopolysaccharidosis type III and fragile X syndrome: protocol for a series of randomized, placebo-controlled N-of-1 trials

BackgroundMany rare genetic neurodevelopmental disorders (RGNDs) are characterized by intellectual disability (ID), severe cognitive and behavioral impairments, potentially diagnosed as a comorbid autism spectrum disorder or attention-deficit hyperactivity disorder. Quality of life is often impaired due to irritability, aggression and self-injurious behavior, generally refractory to standard therapies. There are indications from previous (case) studies and patient reporting that cannabidiol (CBD) may be an effective treatment for severe behavioral manifestations in RGNDs. However, clear evidence is lacking and interventional research is challenging due to the rarity as well as the heterogeneity within and between disease groups and interindividual differences in treatment response. Our objective is to examine the effectiveness of CBD on severe behavioral manifestations in three RGNDs, including Tuberous Sclerosis Complex (TSC), mucopolysaccharidosis type III (MPS III), and Fragile X syndrome (FXS), using an innovative trial design.MethodsWe aim to conduct placebo-controlled, double-blind, block-randomized, multiple crossover N-of-1 studies with oral CBD (twice daily) in 30 patients (aged ≥ 6 years) with confirmed TSC, MPS III or FXS and severe behavioral manifestations. The treatment is oral CBD up to a maximum of 25 mg/kg/day, twice daily. The primary outcome measure is the subscale irritability of the Aberrant Behavior Checklist. Secondary outcome measures include (personalized) patient-reported outcome measures with regard to behavioral and psychiatric outcomes, disease-specific outcome measures, parental stress, seizure frequency, and adverse effects of CBD. Questionnaires will be completed and study medication will be taken at the participants’ natural setting. Individual treatment effects will be determined based on summary statistics. A mixed model analysis will be applied for analyzing the effectiveness of the intervention per disorder and across disorders combining data from the individual N-of-1 trials.DiscussionThese N-of-1 trials address an unmet medical need and will provide information on the effectiveness of CBD for severe behavioral manifestations in RGNDs, potentially generating generalizable knowledge at an individual-, disorder- and RGND population level.Trial registrationEudraCT: 2021-003250-23, registered 25 August 2022, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-003250-23/NL.

Subependymal giant cell astrocytoma (SEGA), unrelated to tuberous sclerosis, NTRK positive

Subependymal giant cell astrocytoma (SEGA), unrelated to tuberous sclerosis, NTRK positive

Healthcare provider recognition of pregnancy related risks and management considerations in patients with tuberous sclerosis complex

BackgroundPatients with tuberous sclerosis complex (TSC) face an increased risk of maternal health complications and worsening disease manifestations during pregnancy. There are no established consensus guidelines that address the management of pregnancy in patients with TSC and healthcare providers rely on their individual experiences and preferences to derive treatment decisions. We sought to obtain provider opinion of pregnancy related maternal complications in patients with TSC, and the common evaluation and management strategies used to address these issues.MethodsWe conducted a cross-sectional survey of healthcare providers with diverse areas of expertise related to the multisystem nature of involvement in TSC. Descriptive analyses were used to analyze our three primary variables: (1) provider recognition of maternal risks/complications; (2) provider recommendations before and during pregnancy; and (3) provider/clinic protocols.ResultsWe received responses from 87 providers from 11 countries, with 40.7% (n = 35) seeing > 30 TSC patients yearly. The majority of providers (n = 70, 88.6%) deemed that a patient with TSC needed expert care beyond the standard of care for a typical pregnancy, with over 25% of providers reporting that they have seen lymphangioleiomyomatosis (LAM) exacerbation, seizures, and preterm labor in pregnant patients with TSC. Providers who managed patients treated with mTOR inhibitors (mTORi) also agreed that mTORi use should be stopped prior to pregnancy (n = 45, 68.2%) but there was uncertainty about when to stop the mTORi (one month 28.9%, two months 11.1%, three months 42.2%, and 6–12 months 2.2%). Additionally, there were mixed opinions on restarting mTORi in response to disease progression during pregnancy. When asked about provider or clinic specific protocols, 71.6% (n = 53) of providers stated that they do not have a clear protocol for management decisions for patients with TSC before or during pregnancy.ConclusionHealthcare providers recognize that patients with TSC are at an increased risk for maternal health complications during pregnancy. However, there are wide inter-individual variances in practice, especially pertaining to decisions regarding mTORi use. There is a critical need to better understand the implications of pregnancy for patients with TSC, and to draft consensus recommendations to guide management decisions.

Bibliometric analysis and network visualization on Tuberous Sclerosis Complex

Background: Tuberous sclerosis complex (TSC) is a rare autosomal dominant multisystem disease resulting from hyperactivation of the mammalian target of rapamycin (mTOR) signaling pathway. This study aimed to measure the quantitative impact of publications in TSC.&#x0D; Materials and methods: We analysed TSC literature obtained from the Scopus database using Bibliometrix R Package and VOSviewer software. Annual publication trends, most productive and collaborative authors/institutions/ countries, most cited articles, most popular journals and author’s keywords were presented using standard bibliometric indicators.&#x0D; Results and discussion: A total of 5375 documents on TSC were published from 1960 to December 2020, with an increasing trend. The three primary contributing writers were Curatolo P, Kwiatkowski DJ, and Thiele EA, with the United States and its institutions being the largest contributor. The research identified two of the most referenced papers as TSC’s seminal pieces. The top journals that published TSC research were medical journals, namely Journal of Child Neurology, Epilepsia, and Pediatric Neurology. mTOR inhibitor, everolimus, sirolimus, mTORC1, mTOR pathway, autophagy, inflammation, infant, intellectual disability, white matter, TSC-associated neuropsychiatric disorders, TOSCA and quality of life were relatively newer author’s keywords and may indicate the future research hotspots in TSC research.&#x0D; Conclusion: Over the last few decades, TSC research has grown in importance, particularly in the field of clinical medicine. Therapeutic components targeting TSC-related pathways, the utilisation of TSC as disease models and long-term safety studies will be future research areas.&#x0D; Bangladesh Journal of Medical Science Vol. 23 No. 01 January’24 Page : 18-28

Topical Sirolimus for Facial Angiofibroma in Tuberous Sclerosis Complex: A Case Series

Facial angiofibromas (FAs) are a distressing manifestation of Tuberous Sclerosis Complex (TSC), often leading to significant physical and psychological burdens. Traditional treatment modalities have limitations, prompting the exploration of alternative therapies. In the present case series, topical sirolimus, a Mammalian Target of Rapamycin (mTOR) inhibitor, was used to manage FAs associated with TSC. Four cases (1 male and 3 female) of FAs in patients with TSC were treated with 0.1% sirolimus ointment applied once daily. The Facial Angiofibroma Severity Index (FASI) was utilised to assess FA severity at baseline and during follow-up visits, which spanned 3 to 12 months. Patient satisfaction and tolerability were also evaluated. Results demonstrated a consistent reduction in FASI scores across all patients, indicating improved FA severity. Patient satisfaction varied, with higher contentment observed in cases where treatment was initiated at a younger age. Importantly, no significant adverse effects were noted, affirming the safety profile of topical sirolimus. These findings underscore the potential of topical sirolimus as a promising therapeutic avenue for FAs in TSC, offering a cost-effective and well-tolerated alternative to conventional treatments. Further research is warranted to elucidate optimal dosing strategies and long-term outcomes, but current evidence supports its consideration as a viable option in the management of FAs associated with TSC.

TRF-27 competitively Binds to G3BPs and Activates MTORC1 to Enhance HER2 Positive Breast Cancer Trastuzumab Tolerance.

About 20% of breast cancer patients are positive for HER2. The efficacy of current treatments is limited by primary and secondary resistance to trastuzumab. tRNA-derived fragments (tRFs) have shown crucial regulatory roles in various cancers. This study aimed to evaluate the role of tRF-27 in regulating the resistance of HER2-positive breast cancer against trastuzumab. tRF-27 was highly expressed in trastuzumab-resistant cells, and its expression level could predict the resistance to trastuzumab. High expression of tRF-27 promoted the growth and proliferation of trastuzumab-exposed cells. RNA-pulldown assay and mass spectrometry were performed to identify Ras GTPase-activating protein-binding proteins 1 and 2 (G3BPs) (two proteins targeted by tRF-27); RNA-immunoprecipitation (RIP) to confirm their bindings; co-immunoprecipitation (co-IP) and RNA-pulldown assay to determine the binding domains between G3BPs and tRF-27.tRF-27 bound to the nuclear transport factor 2 like domain(NTF2 domain) of G3BPs through a specific sequence. tRF-27 relied on G3BPs and NTF2 domain to increase trastuzumab tolerance. tRF-27 competed with lysosomal associated membrane protein 1(LAMP1) for NTF2 domain, thereby inhibiting lysosomal localization of G3BPs and tuberous sclerosis complex (TSC). Overexpression of tRF-27 inhibited phosphorylation of TSCs and promoted the activation of mechanistic target of rapamycin complex 1(MTORC1) to enhance cell proliferation and entice the resistance of HER2-positive breast cancer against trastuzumab.

Kiosk 9Q-FA-07 - Are Cardiac Fatty Deposits in Tuberous Sclerosis Complex Really Benign?

Kiosk 9Q-FA-07 - Are Cardiac Fatty Deposits in Tuberous Sclerosis Complex Really Benign?

Differentially gene expression profiling reveals effect similarities of everolimus, asiaticoside, and asiatic acid on TSC-derived renal angiomyolipoma

Tuberous sclerosis complex (TSC) is a rare genetic disorder characterized by the development of benign hamartomas in various organs, including renal angiomyolipoma. The current medical standard treatment for TSC-associated renal angiomyolipoma involves the use of a mammalian target of rapamycin (mTOR) inhibitor. To better understand the molecular basis of this treatment approach, our study aimed to identify differentially expressed genes (DEGs) in the UMB1949 cell line following treatment with asiaticoside and asiatic acid and compared them to the effects of everolimus treatment. Using the RT2 Profiler polymerase chain reaction (PCR) array panel, we systematically analyzed the expression patterns of these DEGs, utilizing gene ontology (GO) terms and Kyoto encyclopedia of genes and genomes (KEGGs) pathway analyses to elucidate the underlying mTOR inhibitory mechanisms in UMB1949. Our results revealed that all three substances shared five DEGs (four upregulated: CAB39, PRKCE, RRAGC, RPS6KA5, and one downregulated: DEPTOR), as well as seven common GO terms and KEGG pathways, suggesting that the inhibitory activity against mTOR closely mirrors that of everolimus. Moreover, we identified a significant overlap in DEGs involved in cell inhibition via the mTOR pathway across all treated groups. Based on the comprehensive analysis of DEG bioinformatics data, we hypothesized that asiaticoside and asiatic acid exhibit functions comparable to everolimus, with asiaticoside displaying a closer similarity to everolimus than asiatic acid. These findings provide valuable insights into the molecular mechanisms and potential mTOR inhibitors for TSC-associated renal angiomyolipoma and establish a crucial link between our study and the current therapeutic landscape of TSC.

Mammalian target of rapamycin inhibitors: A new-possible approach for in-utero medication therapy.

The mammalian/mechanistic target of rapamycin (mTOR) is a protein kinase that plays a crucial role in regulating cellular growth, metabolism, and survival. Although there is no absolute contraindication for the use of mTOR inhibitors during pregnancy, the specific fetal effects remain unknown. Available data from the past 2decades have examined the use of mTOR inhibitors during pregnancy in patients with solid organ transplantation, showing no clear link to fetal complications or structural abnormalities. Recently, a handful of case reports and series have described transplacental therapy of mTOR inhibitors to control symptomatic and complicated pathologies in the fetus. The effect of these agents includes a significant reduction in lesion size in the fetus and a reduced need for mechanical ventilation in neonates. In this context, we delve into the potential of mTOR inhibitors as in-utero therapy for fetal abnormalities, with a primary focus on lymphatic malformation (LM) and cardiac rhabdomyoma (CR). While preliminary reports underscore the efficacy of mTOR inhibitors for the treatment of fetal CR and fetal brain lesions associated with tuberous sclerosis complex, chylothorax, and LMs, additional investigation and clinical trials are essential to comprehensively assess the safety and efficacy of these medications.

MECP2 gene; infant movement and autism; white-matter differences in tuberous sclerosis

MECP2 gene; infant movement and autism; white-matter differences in tuberous sclerosis

Клинический случай новой коронавирусной инфекции (COVID-19) с летальным исходом у пациентки с туберозным склерозом

Клинический случай новой коронавирусной инфекции (COVID-19) с летальным исходом у пациентки с туберозным склерозом

Naked cuticle homolog 2 controls the differentiation of osteoblasts and osteoclasts and ameliorates bone loss in ovariectomized mice

Naked cuticle homolog 2 (NKD2) has been recognized as an antagonist of Wnt/β-catenin signaling and a tumor suppressor. The role of NKD2 in osteoblast and osteoclast differentiation and the mechanism are not fully understood. In this study, we identified the up-regulation of NKD2 during osteoblast and adipocyte differentiation. Functional experiments revealed that NKD2 stimulated osteoblast differentiation and suppressed adipocyte formation. Furthermore, NKD2 down-regulated the expression of receptor activator of nuclear factor-κB ligand in bone marrow mesenchymal stem cells and inhibited osteoclast formation from osteoclast precursor cells. Mechanistic investigations revealed that the regulation of osteoblast and adipocyte differentiation by NKD2 involved Wnt/β-catenin and tuberous sclerosis complex subunit 1 (TSC1)/mechanistic target of rapamycin complex 1 (mTORC1) signaling pathways. Unlike in undifferentiated mesenchymal cells where NKD2 promoted Dishevelled-1 degradation, in the cells differentiating toward osteoblasts or adipocytes NKD2 down-regulated secreted frizzled related protein 1/4 expression and failed to destabilize Dishevelled-1, thereby activating Wnt/β-catenin signaling. Moreover, NKD2 bound to TSC1 and inhibited mTORC1 signaling. Further investigation uncovered an interplay between TSC1/mTORC1 and Wnt/β-catenin signaling pathways. Finally, transplantation of NKD2-overexpressing bone marrow mesenchymal stem cells into the marrow of mice increased osteoblasts, reduced osteoclasts and marrow fat, and partially prevented bone loss in ovariectomized mice. This study provides evidence that NKD2 in mesenchymal stem/progenitor cells reciprocally regulates the differentiation of osteoblasts and adipocytes by modulating Wnt/β-catenin and mTORC1 pathways and inhibits osteoclast formation by down-regulating receptor activator of nuclear factor-κB ligand. It suggests that NKD2 up-regulation may ameliorate postmenopausal bone loss.

Hyperactive mTORC1 in striatum dysregulates dopamine receptor expression and odor preference behavior.

Mechanistic target of rapamycin (mTOR) plays an important role in brain development and synaptic plasticity. Dysregulation of the mTOR pathway is observed in various human central nervous system diseases, including tuberous sclerosis complex, autism spectrum disorder (ASD), and neurodegenerative diseases, including Parkinson's disease and Huntington's disease. Numerous studies focused on the effects of hyperactivation of mTOR on cortical excitatory neurons, while only a few studies focused on inhibitory neurons. Here we generated transgenic mice in which mTORC1 signaling is hyperactivated in inhibitory neurons in the striatum, while cortical neurons left unaffected. The hyperactivation of mTORC1 signaling increased GABAergic inhibitory neurons in the striatum. The transgenic mice exhibited the upregulation of dopamine receptor D1 and the downregulation of dopamine receptor D2 in medium spiny neurons in the ventral striatum. Finally, the transgenic mice demonstrated impaired motor learning and dysregulated olfactory preference behavior, though the basic function of olfaction was preserved. These findings reveal that the mTORC1 signaling pathway plays an essential role in the development and function of the striatal inhibitory neurons and suggest the critical involvement of the mTORC1 pathway in the locomotor abnormalities in neurodegenerative diseases and the sensory defects in ASD.

Ash leaf iris spot in a case of tuberous sclerosis complex

Ash leaf iris spot in a case of tuberous sclerosis complex

Kiosk 1R-FA-01 - Tuberous Sclerosis Clinical Criteria - Are We Ready for Adults’ Hearts?

Kiosk 1R-FA-01 - Tuberous Sclerosis Clinical Criteria - Are We Ready for Adults’ Hearts?

Next-generation variant exon screening: Moving forward in routine genetic disease investigations

PurposePatients with genetic diseases often seek testing to reach a firm diagnosis. Based on clinical phenotypes, exome sequencing for small-nucleotide variations or array-based methods for copy-number variations (CNVs) are commonly offered to identify the underlying causative genetic variants. In this study, we investigated whether data from a standard ES test could be used to additionally identify pathogenic CNVs and increase diagnostic yield. MethodsProspectively, 134 patients presenting with a skin condition suspected of being genetic in origin were offered the next-generation variant exon screening (ngVES) test. Sequencing data were analyzed for both single-nucleotide variants and CNVs using established algorithms. ResultsThe positive detection rate for skin diseases using ngVES was 66% (88/134) with the most common diagnoses being neurofibromatosis type1 (n = 48) and tuberous sclerosis type2 (n = 12). The diagnostic increased yield from 58% to 66% was the result of additional detection of pathogenic CNVs. Each of the 9 CNVs were verified by independent genetic tests. ConclusionThe advances in the ngVES bioinformatics pipeline are proofs of concept, which improved identification of genetic variants associated with skin disease. Simultaneous single-nucleotide variants/INDEL and CNV detection by this approach demonstrates ngVES potential as a first-tier screen for any suspected genetic disease.

Subependymal Gian Cell Astrocytoma in An Adult Without Tuberous Sclerosis Complex: A Neuropathologial Case Report of a Tumor Initially Misdiagnosed as Glioblastoma

Subependymal Gian Cell Astrocytoma in An Adult Without Tuberous Sclerosis Complex: A Neuropathologial Case Report of a Tumor Initially Misdiagnosed as Glioblastoma

Review of the Efficacy and Safety of Cannabidiol with a Focus on Children and Adolescents in the Treatment of Psychiatric Symptoms and Disorders

Abstract: Cannabidiol (CBD) is a plant-derived cannabinoid found in cannabis and hemp plants with broad psychopharmacologic effects and poorly understood mechanisms of action that may include antioxidant and anti-inflammatory properties and central nervous system (CNS) modulation of endocannabinoid, glutamatergic, and serotonergic neurotransmission. This article reviews existing data on the safety and efficacy of CBD for mental and physical health indications in the pediatric population and for psychiatric disorders in adults, with a focus on clinical trials. Searches of PubMed and PsycINFO for articles through October 2021 focused on clinical trials on “cannabidiol” and “seizure” or “psychiatry” in youth and adults, identifying 686 articles that were then screened and evaluated for relevance. Research into the safety and efficacy of CBD led to the United States Food and Drug Administration's approval of Epidolex, a purified pharmaceuticalgrade CBD medicine, for treating drug-resistant seizures in Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Beyond treatment for rare seizure disorders, CBD has received growing public interest in recent years as a “natural” treatment for various other medical and psychiatric conditions, resulting in a rapidly expanding multi-billion-dollar US market for CBD dietary/health supplements and a growing number of Americans reporting regular use. However, the growing demand and broad claims of purported benefits have greatly outpaced the body of literature substantiating its use. Further, limited safety data in pediatric populations, drug-to-drug interactions between CBD and prescribed medications, and issues related to mislabeling and contamination have blunted enthusiasm for CBD in the pediatric healthcare community and indicate a need for additional research.