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Keywords = tuberous-sclerosis-complex-associated neuropsychiatric disorders

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35 pages, 1877 KiB  
Review
Dysregulation of the Cannabinoid System in Childhood Epilepsy: From Mechanisms to Therapy
by Gloria Montebello and Giuseppe Di Giovanni
Int. J. Mol. Sci. 2025, 26(13), 6234; https://doi.org/10.3390/ijms26136234 - 27 Jun 2025
Viewed by 1937
Abstract
Epilepsy affects over 12 million children worldwide, with approximately 30% classified as having drug-resistant epilepsy (DRE), often accompanied by neuropsychiatric comorbidities that severely impact quality of life. The endocannabinoid system (ECS) functions as a multifaceted neuromodulatory network regulating neuronal excitability, synaptic plasticity, and [...] Read more.
Epilepsy affects over 12 million children worldwide, with approximately 30% classified as having drug-resistant epilepsy (DRE), often accompanied by neuropsychiatric comorbidities that severely impact quality of life. The endocannabinoid system (ECS) functions as a multifaceted neuromodulatory network regulating neuronal excitability, synaptic plasticity, and immune homeostasis from early life through adolescence and into aging. In pediatric epilepsies, alterations in ECS components, particularly CB1 receptor expression and endocannabinoid levels, reveal disorder-specific vulnerabilities and therapeutic opportunities. Cannabidiol (CBD), a non-psychoactive compound from Cannabis sativa, has shown strong preclinical and clinical efficacy in treating DRE and is approved for Dravet syndrome, Lennox–Gastaut syndrome, and Tuberous Sclerosis Complex. Other ECS-based strategies, such as the use of CB1 receptor-positive allosteric modulators, can selectively enhance endogenous cannabinoid signaling where and when it is active, potentially reducing seizures in conditions like Dravet and absence epilepsy. Similarly, FAAH and MAGL inhibitors may help restore ECS tone without directly activating CB1 receptors. Precision targeting of ECS components based on regional expression and syndrome-specific pathophysiology may optimize seizure control and associated comorbidities. Nonetheless, long-term pediatric use must be approached with caution, given the critical role of the ECS in brain development. Full article
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8 pages, 947 KiB  
Case Report
The Therapeutic Potential of Oral Everolimus for Facial Angiofibromas in Pediatric Tuberous Sclerosis Complex: A Case-Based Analysis of Efficacy
by George Imataka, Satoshi Mori, Kunio Yui, Ken Igawa, Hideaki Shiraishi and Shigemi Yoshihara
Diseases 2024, 12(12), 334; https://doi.org/10.3390/diseases12120334 - 20 Dec 2024
Cited by 1 | Viewed by 1278
Abstract
Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by mutations in the TSC1 and TSC2 genes, leading to the dysregulation of the mammalian target of rapamycin (mTOR) pathway. This dysregulation results in the development of benign tumors across multiple [...] Read more.
Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by mutations in the TSC1 and TSC2 genes, leading to the dysregulation of the mammalian target of rapamycin (mTOR) pathway. This dysregulation results in the development of benign tumors across multiple organ systems and poses significant neurodevelopmental challenges. The clinical manifestations of TSC vary widely and include subependymal giant cell astrocytomas (SEGAs), renal angiomyolipomas (AMLs), facial angiofibromas (FAs), and neuropsychiatric conditions such as autism spectrum disorder (ASD). mTOR inhibitors, notably everolimus, have become central to TSC management, with documented efficacy in reducing the sizes of SEGAs and AMLs and showing promise in addressing additional TSC-related symptoms. Case Presentation: We report the case of an 11-year-old male diagnosed with TSC, presenting with hallmark features including hypopigmented macules, early-onset infantile spasms, SEGA, and AMLs. Initial interventions included adrenocorticotropic hormone (ACTH) therapy and sodium valproate for seizure management and a minimally invasive keyhole craniotomy for SEGA reduction. At age 12, oral everolimus therapy was introduced to address both SEGA recurrence risk and ASD-related social deficits. Over the course of 24 weeks, a reduction in the size and erythema of the patient’s FAs was observed, alongside improvements in social engagement, suggesting potential added benefits of systemic mTOR inhibition beyond tumor control. Results: Treatment with everolimus over a 24-month period led to significant reductions in both FA and AML size, as well as measurable improvements in ASD-associated behaviors. Therapeutic drug monitoring maintained serum levels within the effective range, minimizing adverse effects and underscoring the tolerability and feasibility of long-term everolimus administration. Conclusions: This case underscores the efficacy of oral everolimus in reducing FA size in a pediatric TSC patient, with broader therapeutic benefits that support the potential of mTOR inhibition as a multi-targeted strategy for TSC management. Further studies are needed to explore the full range of applications and long-term impact of mTOR inhibitors in TSC care. Full article
(This article belongs to the Section Oncology)
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11 pages, 4509 KiB  
Case Report
Three-Year Follow-Up after Intrauterine mTOR Inhibitor Administration for Fetus with TSC-Associated Rhabdomyoma
by Anita Maász, Tímea Bodó, Ágnes Till, Gábor Molnár, György Masszi, Gusztáv Labossa, Zsuzsanna Herbert, Judit Bene and Kinga Hadzsiev
Int. J. Mol. Sci. 2023, 24(16), 12886; https://doi.org/10.3390/ijms241612886 - 17 Aug 2023
Cited by 7 | Viewed by 2330
Abstract
Tuberous sclerosis complex (TSC) is a multisystem disorder characterized by seizures, neuropsychiatric disorders, and tumors of the heart, brain, skin, lungs, and kidneys. We present a three-year follow-up of a patient with TSC-associated rhabdomyoma detected in utero. Genetic examination of the fetus and [...] Read more.
Tuberous sclerosis complex (TSC) is a multisystem disorder characterized by seizures, neuropsychiatric disorders, and tumors of the heart, brain, skin, lungs, and kidneys. We present a three-year follow-up of a patient with TSC-associated rhabdomyoma detected in utero. Genetic examination of the fetus and the parents revealed a de novo variant in the TSC2 gene (c.3037delG, p.Asp1013IlefsTer3). Oral everolimus was initiated in the pregnant mother to regress the fetal tumor, which was successful. To the best of our knowledge, there is very little information regarding the use of everolimus therapy during pregnancy. West-syndrome was diagnosed when the proband was four months old. The symptoms were well-manageable, however temporarily. Therapy-resistant focal seizures were frequent. The patient had good vitals and was under regular cardiological control, showed a balanced circulation, and did not require any medication. Subependymal giant cell astrocytoma (SEGA) identified by regular neuroimaging examinations remained unchanged, which may be a consequence of early intrauterine treatment. Early detection of the pathogenic TSC2 variant, followed by in utero administration of everolimus and early vigabatrin therapy, allowed the detection of a milder developmental delay of the proband. Our study emphasizes how early genetic testing and management of epilepsy are pivotal for proper neurodevelopmental impacts and therapeutic strategies. Full article
(This article belongs to the Special Issue Molecular and Genetic Studies in Neurocutaneous Syndromes)
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13 pages, 297 KiB  
Article
Tuberous Sclerosis Complex Patients’ Needs and Difficulties—Results of TAND Questionnaire Analysis in Polish Adult Population
by Anna B. Marcinkowska, Sergiusz Jóźwiak, Agnieszka Tarasewicz, Alicja Dębska-Ślizień and Edyta Szurowska
J. Clin. Med. 2022, 11(21), 6536; https://doi.org/10.3390/jcm11216536 - 3 Nov 2022
Cited by 7 | Viewed by 2120
Abstract
Introduction: Tuberous Sclerosis Complex (TSC) is a rare genetic disease. Around 90% of individuals with TSC present some neuropsychiatric manifestations (TSC-associated neuropsychiatric disorders, TAND). To date, none of the studies have focused on the TAND profile of the adult population. Thus, the aim [...] Read more.
Introduction: Tuberous Sclerosis Complex (TSC) is a rare genetic disease. Around 90% of individuals with TSC present some neuropsychiatric manifestations (TSC-associated neuropsychiatric disorders, TAND). To date, none of the studies have focused on the TAND profile of the adult population. Thus, the aim of the study was to describe their potential specific needs and difficulties, including differences in cohorts with or without epilepsy and/or intellectual disability. Method: The Polish version of the TAND Checklist was used for assessment of individuals with TSC. Participants had to meet the criteria for diagnosis of TSC. One hundred adult participants (forty-eight males/ fifty-two females; mean age 32.33 ± 11.29) were enrolled in the study. Epilepsy was present in 71% of patients; intellectual disability occurred in a total of 37%. Results: Only 11% of individuals received complete TAND features examination in the past. Moreover, 91.5 of the subjects had four and more TAND symptoms. Intellectually disabled patients and those with epilepsy had more neuropsychiatric problems than epilepsy-free subjects. Conclusions: Findings reveal that TANDs are common in adults with TSC and are underdiagnosed. Most individuals present several behavioural and cognitive problems. Among psychiatric disorders, the most common are ASD, depression, and anxiety disorder. TAND screening should be widely disseminated and applied in clinical practice for early identification, prevention, and rehabilitation of their difficulties. TAND is one of the most significant issues affecting the quality of life of TSC patients and their carers. Full article
(This article belongs to the Section Clinical Neurology)
17 pages, 1275 KiB  
Article
miRNAs and isomiRs: Serum-Based Biomarkers for the Development of Intellectual Disability and Autism Spectrum Disorder in Tuberous Sclerosis Complex
by Mirte Scheper, Alessia Romagnolo, Zein Mersini Besharat, Anand M. Iyer, Romina Moavero, Christoph Hertzberg, Bernhard Weschke, Kate Riney, Martha Feucht, Theresa Scholl, Borivoj Petrak, Alice Maulisova, Rima Nabbout, Anna C. Jansen, Floor E. Jansen, Lieven Lagae, Malgorzata Urbanska, Elisabetta Ferretti, Aleksandra Tempes, Magdalena Blazejczyk, Jacek Jaworski, David J. Kwiatkowski, Sergiusz Jozwiak, Katarzyna Kotulska, Krzysztof Sadowski, Julita Borkowska, Paolo Curatolo, James D. Mills, Eleonora Aronica and EPISTOP Consortium Membersadd Show full author list remove Hide full author list
Biomedicines 2022, 10(8), 1838; https://doi.org/10.3390/biomedicines10081838 - 29 Jul 2022
Cited by 10 | Viewed by 4239
Abstract
Tuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterized by a high incidence of epilepsy and neuropsychiatric manifestations known as tuberous-sclerosis-associated neuropsychiatric disorders (TANDs), including autism spectrum disorder (ASD) and intellectual disability (ID). MicroRNAs (miRNAs) are small regulatory non-coding RNAs that [...] Read more.
Tuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterized by a high incidence of epilepsy and neuropsychiatric manifestations known as tuberous-sclerosis-associated neuropsychiatric disorders (TANDs), including autism spectrum disorder (ASD) and intellectual disability (ID). MicroRNAs (miRNAs) are small regulatory non-coding RNAs that regulate the expression of more than 60% of all protein-coding genes in humans and have been reported to be dysregulated in several diseases, including TSC. In the current study, RNA sequencing analysis was performed to define the miRNA and isoform (isomiR) expression patterns in serum. A Receiver Operating Characteristic (ROC) curve analysis was used to identify circulating molecular biomarkers, miRNAs, and isomiRs, able to discriminate the development of neuropsychiatric comorbidity, either ASD, ID, or ASD + ID, in patients with TSC. Part of our bioinformatics predictions was verified with RT-qPCR performed on RNA isolated from patients’ serum. Our results support the notion that circulating miRNAs and isomiRs have the potential to aid standard clinical testing in the early risk assessment of ASD and ID development in TSC patients. Full article
(This article belongs to the Section Neurobiology and Clinical Neuroscience)
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16 pages, 928 KiB  
Review
PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic Diseases
by Petra Hillmann and Doriano Fabbro
Int. J. Mol. Sci. 2019, 20(22), 5792; https://doi.org/10.3390/ijms20225792 - 18 Nov 2019
Cited by 75 | Viewed by 9205
Abstract
The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway has been implicated as a cancer target. Big pharma players and small companies have been developing small molecule inhibitors of PI3K and/or mTOR since the 1990s. Although four inhibitors have been approved, many [...] Read more.
The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway has been implicated as a cancer target. Big pharma players and small companies have been developing small molecule inhibitors of PI3K and/or mTOR since the 1990s. Although four inhibitors have been approved, many open questions regarding tolerability, patient selection, sensitivity markers, development of resistances, and toxicological challenges still need to be addressed. Besides clear oncological indications, PI3K and mTOR inhibitors have been suggested for treating a plethora of different diseases. In particular, genetically induced PI3K/mTOR pathway activation causes rare disorders, known as overgrowth syndromes, like PTEN (phosphatase and tensin homolog) hamartomas, tuberous sclerosis complex (TSC), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth spectrum (PROS), and activated PI3-Kinase delta syndrome (PI3KCD, APDS). Some of those disorders likeTSC or hemimegalencephaly, which are one of the PROS disorders, also belong to a group of diseases called mTORopathies. This group of syndromes presents with additional neurological manifestations associated with epilepsy and other neuropsychiatric symptoms induced by neuronal mTOR pathway hyperactivation. While PI3K and mTOR inhibitors have been and still are intensively tested in oncology indications, their use in genetically defined syndromes and mTORopathies appear to be promising avenues for a pharmacological intervention. Full article
(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target)
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