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Stem Cell Research Jun 2024Tuberous Sclerosis Complex (TSC) is a severe developmental disorder with various clinical effects, primarily caused by TSC2 gene mutations, often involving loss of...
Tuberous Sclerosis Complex (TSC) is a severe developmental disorder with various clinical effects, primarily caused by TSC2 gene mutations, often involving loss of function(Henske,et al., 2016).To explore role of TSC2 in human heart development, we successfully developed a TSC2 knockout (TSC2-/-) human embryonic stem cells (hESCs) line using CRISPR/Cas9 gene editing. This TSC2-/- hESC line maintained a normal karyotype, expressed pluripotency markers strongly, and could differentiate into all three germ layers in vivo. This cell line will be a valuable tool for future research on the role of TSC2 in heart development.
Topics: Humans; Tuberous Sclerosis Complex 2 Protein; CRISPR-Cas Systems; Gene Editing; Human Embryonic Stem Cells; Cell Line; Gene Knockout Techniques; Cell Differentiation
PubMed: 38574666
DOI: 10.1016/j.scr.2024.103399 -
Neuromolecular Medicine Apr 2024The manifestations of tuberous sclerosis complex (TSC) in humans include epilepsy, autism spectrum disorders (ASD) and intellectual disability. Previous studies...
The manifestations of tuberous sclerosis complex (TSC) in humans include epilepsy, autism spectrum disorders (ASD) and intellectual disability. Previous studies suggested the linkage of TSC to altered cerebral blood flow and metabolic dysfunction. We previously reported a significant elevation in cerebral blood flow in an animal model of TSC and autism of young Eker rats. Inhibition of the mammalian target of rapamycin (mTOR) by rapamycin could restore normal oxygen consumption and cerebral blood flow. In this study, we investigated whether inhibiting a component of the mTOR signaling pathway, p70 ribosomal S6 kinase (S6K1), would yield comparable effects. Control Long Evans and Eker rats were divided into vehicle and PF-4708671 (S6K1 inhibitor, 75 mg/kg for 1 h) treated groups. Cerebral regional blood flow (C-iodoantipyrine) was determined in isoflurane anesthetized rats. We found significantly increased basal cortical (+ 32%) and hippocampal (+ 15%) blood flow in the Eker rats. PF-4708671 significantly lowered regional blood flow in the cortex and hippocampus of the Eker rats. PF-4708671 did not significantly lower blood flow in these regions in the control Long Evans rats. Phosphorylation of S6-Ser240/244 and Akt-Ser473 was moderately decreased in Eker rats but only the latter reached statistical significance upon PF-4708671 treatment. Our findings suggest that moderate inhibition of S6K1 with PF-4708671 helps to restore normal cortical blood flow in Eker rats and that this information might have therapeutic potential in tuberous sclerosis complex and autism.
Topics: Animals; Humans; Rats; Autistic Disorder; Mammals; Phosphorylation; Rats, Long-Evans; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis
PubMed: 38570425
DOI: 10.1007/s12017-024-08780-7 -
Cureus Mar 2024Renal angiomyolipoma (AML) is a rare benign tumor of the kidney that can occur as a sporadic lesion or a part of tuberous sclerosis. A 77-year-old female patient with a...
Renal angiomyolipoma (AML) is a rare benign tumor of the kidney that can occur as a sporadic lesion or a part of tuberous sclerosis. A 77-year-old female patient with a history of hypertension, hyperlipidemia, and an unclear history of left nephrectomy in 1999 presented with progressive shortness of breath and palpitations. Her vital signs showed elevated blood pressure, and the examination was benign and non-focal. A work-up showed multiple lesions in her lungs and right kidney, representing lymphangioleiomyomatosis. The patient was diagnosed with tuberous sclerosis and was followed up by pulmonology and nephrology. She underwent embolization of the renal AML, after which her blood pressure (BP) was more controlled, and she reported feeling well and symptom-free. Renal AML, as a part of tuberous sclerosis, is a rare cause of secondary hypertension. Embolization of AML is effective in controlling BP.
PubMed: 38567223
DOI: 10.7759/cureus.55410 -
Autopsy & Case Reports 2024The present work reports the autopsy findings of a unique case characterized by fatal retroperitoneal hemorrhage following the traumatic rupture of bilateral renal...
The present work reports the autopsy findings of a unique case characterized by fatal retroperitoneal hemorrhage following the traumatic rupture of bilateral renal angiomyolipomas. Renal angiomyolipomas are generally benign tumors with an unpredictable clinical course, ranging from asymptomatic to sudden rupture and hemorrhagic shock. They may be associated with genetic disorders such as tuberous sclerosis complex. The case under investigation is unprecedented in the medical literature due to its bilateral nature and fatal outcome. Autopsy analysis revealed an extensive retroperitoneal hemorrhage originating from bilateral ruptured tumors. Microscopic examination found features consistent with bilateral renal angiomyolipoma. Circumstantial information identified a traffic accident before the death, considering it as the cause of the tumors' traumatic rupture. In this case, due to the severity of the situation, immediate medical measures-such as fluid resuscitation, coagulopathy correction, and surgical treatment, which are usually lifesaving-could not be performed. This led to the patient being declared dead at the scene of the crash.
PubMed: 38562647
DOI: 10.4322/acr.2024.482 -
Clinical Case Reports Apr 2024Abdominal aortic aneurysm complicated by tuberous sclerosis is rare, particularly in patients over the age of 10. It is important to screen for abdominal aortic aneurysm...
KEY CLINICAL MESSAGE
Abdominal aortic aneurysm complicated by tuberous sclerosis is rare, particularly in patients over the age of 10. It is important to screen for abdominal aortic aneurysm in adolescents diagnosed with tuberous sclerosis regularly.
ABSTRACT
A 15-year-old girl who was diagnosed with tuberculous sclerosis complicated with a saccular aortic abdominal aneurysm (AAA), measuring 19 × 18 mm in diameter. The patient underwent open repair of AAA using a 11 mm straight prosthetic graft. It is important to screen for AAA in adolescents diagnosed with tuberous sclerosis regularly.
PubMed: 38562571
DOI: 10.1002/ccr3.8715 -
Epilepsy & Behavior : E&B May 2024Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC)-associated epilepsy are rare conditions associated with severe childhood-onset...
A quantitative cross-sectional study of the burden of caring for patients with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex-associated epilepsy in Japan.
INTRODUCTION
Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC)-associated epilepsy are rare conditions associated with severe childhood-onset epilepsy. Caregivers play a critical role in the patients' care and may experience significant psychosocial and socioeconomic burden. This cross-sectional study determined the burden of caring for patients with these rare epilepsy conditions in Japan.
METHODS
A quantitative online survey was used to assess patients' and caregivers' characteristics and the caregivers' emotional state, among others. Several validated questionnaires were used: the Hospital Anxiety and Depression Scale (HADS; 0-21 score) assessed the caregivers' emotional wellbeing, the Pediatric Quality of Life Inventory Family Impact Module (PedsQL FIM; 0-100 score) assessed the health-related quality of life (HRQoL) of the caregivers and their families, and the Work Productivity and Activity Impairment General Health (WPAI:GH; 0-100 % score) questionnaire assessed work productivity.
RESULTS
A total of 36 caregivers responded (median [interquartile range (IQR)] age 43.5 [39.5, 48.3] years; 33/36 [92 %] female; 13/36 [36 %] working part-time and 13/36 [36 %] not working). Participants cared for 7/36 (19 %), 19/36 (53 %), and 10/36 (28 %) patients with LGS, DS, and TSC, respectively (median [IQR] age, 11.0 [6.8, 16.3] years; age at first seizure, 0 [0, 0] years). Patients received a median (IQR) of 4 (3, 5) treatment drug types. Patients experienced median (IQR) 3.0 (0, 21.0) epileptic seizures in the previous week; 28/36 (78 %) had severe intellectual disabilities, and 34/36 (94 %) had developmental delays. Caregivers reported stress (17/36 [47 %]), sleep problems (13/36 [36 %]), and anxiety (12/36 [33 %]). They spent a median (IQR) of 50.0 (17.5, 70.0) hours caregiving in the previous week, with 3.0 (1.0, 11.0) hours of seizure-specific care. Caregivers reported that their lives would be easier with a median (IQR) of 1.5 (0, 5.0) hours fewer per week caring for patients during/following seizures. Median HADS scores were 9.5 ('suspected anxiety diagnosis') and 7.5 ('no depression') for caregivers, and PedsQL FIM Total median score was 60.1, indicating HRQoL impairment for the caregiver and their family. WPAI:GH scores for paid workers indicated important work impairment. Higher caregiving hours (≥ 21 h vs. < 21 h in the previous week) resulted in higher caregiver burden as indicated by the HADS Total score (p = 0.0062) and PedsQL FIM Total score (p = 0.0007).
CONCLUSIONS
Caregivers of patients with LGS, DS, or TSC in Japan experience a significant time burden, reduced HRQoL, and high level of work/activity impairment. Caregivers provide round-the-clock care to patients and rely on family and specialized caring services to help manage the increased caregiving time, which tends to be associated with greater emotional burden and HRQoL impact.
Topics: Humans; Female; Male; Cross-Sectional Studies; Tuberous Sclerosis; Japan; Adult; Caregivers; Middle Aged; Quality of Life; Lennox Gastaut Syndrome; Epilepsies, Myoclonic; Child; Adolescent; Surveys and Questionnaires; Epilepsy; Cost of Illness; Young Adult; Child, Preschool
PubMed: 38555725
DOI: 10.1016/j.yebeh.2024.109741 -
Archives of Pathology & Laboratory... Mar 2024Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors of uncertain histogenesis expressing smooth muscle and melanocytic markers. The...
CONTEXT.—
Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors of uncertain histogenesis expressing smooth muscle and melanocytic markers. The clinicopathologic spectrum in young patients is not well documented.
OBJECTIVE.—
To describe a multi-institutional series of PEComas in children, adolescents, and young adults.
DESIGN.—
PEComas, not otherwise specified (NOS); angiomyolipomas (AMLs); lymphangioleiomyomatosis; and clear cell sugar tumors were retrospectively identified from 6 institutions and authors' files.
RESULTS.—
Seventy PEComas in 64 patients (median age, 15 years) were identified. They were more common in females (45 of 64 patients), occurring predominately in kidney (53 of 70), followed by liver (6 of 70). Thirty-four patients had confirmed tuberous sclerosis complex (TSC), 3 suspected TSC mosaicism, 2 Li-Fraumeni syndrome (LFS) and 1 neurofibromatosis type 1. Most common variants were classic (49 of 70) and epithelioid (8 of 70) AML. Among patients with AMLs, most (34 of 47) had TSC, and more TSC patients had multiple AMLs (15 of 36) than non-TSC patients (2 of 13). Two TSC patients developed malignant transformation of classic AMLs: 1 angiosarcomatous and 1 malignant epithelioid. Lymphangioleiomyomatosis (5 of 70) occurred in females only, usually in the TSC context (4 of 5). PEComas-NOS (6 of 70) occurred exclusively in non-TSC patients, 2 of whom had LFS (2 of 6). Three were malignant, 1 had uncertain malignant potential, and 2 were benign. All 4 PEComas-NOS in non-LFS patients had TFE3 rearrangements.
CONCLUSIONS.—
Compared to the general population, TSC was more prevalent in our cohort; PEComas-NOS showed more frequent TFE3 rearrangements and possible association with LFS. This series expands the spectrum of PEComas in young patients and demonstrates molecular features and germline contexts that set them apart from older patients.
PubMed: 38547914
DOI: 10.5858/arpa.2023-0552-OA -
Cureus Feb 2024Tuberous sclerosis complex (TSC) is a neurocutaneous disease that manifests across multiple body systems. While there are substantial guidelines and protocols for...
Tuberous sclerosis complex (TSC) is a neurocutaneous disease that manifests across multiple body systems. While there are substantial guidelines and protocols for managing the physical presentation of the disease, managing the psychosocial factors and the adverse effects as a social determinant of health is complex and unclear. This study discusses a patient with TSC who was hospitalized for pneumonia and how both her psychiatric and somatic symptoms were managed. Here we present the case of a 38-year-old Caucasian female with shortness of breath and generalized weakness. She had a past medical history of TSC and pneumothorax. This patient presented to the emergency department agitated and initially combative with her care team. Ultimately, she was administered dexmedetomidine to reduce her agitation. Here we suggest that this patient's agitation and other psychiatric symptoms are intimately related to her diagnosis of TSC. Because of the heavy burden of TSC on the patient's life, the patient's aggressive nature could be an act of displacement of feelings from her medical complications onto her interactions with others. The patient understood that her complications hindered her ability to function as a healthy 38-year-old and perform activities of daily living without severe exhaustion. Just as her condition and its secondary complications hindered her body, feelings of anger and despair hindered her ability to appropriately interact and socialize with others. TSC is a debilitating condition that targets the body and mind. While much research has gone into treating each somatic system it may affect, there is a disconnect between the psychiatric aftermath and the toll that such a condition's psychiatric comorbidities may take on its patients.
PubMed: 38544592
DOI: 10.7759/cureus.54956 -
Genes Mar 2024The mechanistic target of rapamycin (mTOR) pathway serves as a master regulator of cell growth, proliferation, and survival. Upregulation of the mTOR pathway has been... (Review)
Review
The mechanistic target of rapamycin (mTOR) pathway serves as a master regulator of cell growth, proliferation, and survival. Upregulation of the mTOR pathway has been shown to cause malformations of cortical development, medically refractory epilepsies, and neurodevelopmental disorders, collectively described as mTORopathies. Tuberous sclerosis complex (TSC) serves as the prototypical mTORopathy. Characterized by the development of benign tumors in multiple organs, pathogenic variants in or disrupt the TSC protein complex, a negative regulator of the mTOR pathway. Variants in critical domains of the TSC complex, especially in the catalytic TSC2 subunit, correlate with increased disease severity. Variants in less crucial exons and non-coding regions, as well as those undetectable with conventional testing, may lead to milder phenotypes. Despite the assumption of complete penetrance, expressivity varies within families, and certain variants delay disease onset with milder neurological effects. Understanding these genotype-phenotype correlations is crucial for effective clinical management. Notably, 15% of patients have no mutation identified by conventional genetic testing, with the majority of cases postulated to be caused by somatic variants which present complex diagnostic challenges. Advancements in genetic testing, prenatal screening, and precision medicine hold promise for changing the diagnostic and treatment paradigm for TSC and related mTORopathies. Herein, we explore the genetic and molecular mechanisms of TSC and other mTORopathies, emphasizing contemporary genetic methods in understanding and diagnosing the condition.
Topics: Humans; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Mutation; Genetic Testing; TOR Serine-Threonine Kinases
PubMed: 38540392
DOI: 10.3390/genes15030332 -
Bioengineering (Basel, Switzerland) Feb 2024The implementation of three-dimensional tissue engineering concurrently with stem cell technology holds great promise for in vitro research in pharmacology and...
Contractile and Genetic Characterization of Cardiac Constructs Engineered from Human Induced Pluripotent Stem Cells: Modeling of Tuberous Sclerosis Complex and the Effects of Rapamycin.
The implementation of three-dimensional tissue engineering concurrently with stem cell technology holds great promise for in vitro research in pharmacology and toxicology and modeling cardiac diseases, particularly for rare genetic and pediatric diseases for which animal models, immortal cell lines, and biopsy samples are unavailable. It also allows for a rapid assessment of phenotype-genotype relationships and tissue response to pharmacological manipulation. Mutations in the and genes lead to dysfunctional mTOR signaling and cause tuberous sclerosis complex (TSC), a genetic disorder that affects multiple organ systems, principally the brain, heart, skin, and kidneys. Here we differentiated healthy (CC3) and tuberous sclerosis (TSP8-15) human induced pluripotent stem cells (hiPSCs) into cardiomyocytes to create engineered cardiac tissue constructs (ECTCs). We investigated and compared their mechano-elastic properties and gene expression and assessed the effects of rapamycin, a potent inhibitor of the mechanistic target of rapamycin (mTOR). The TSP8-15 ECTCs had increased chronotropy compared to healthy ECTCs. Rapamycin induced positive inotropic and chronotropic effects (i.e., increased contractility and beating frequency, respectively) in the CC3 ECTCs but did not cause significant changes in the TSP8-15 ECTCs. A differential gene expression analysis revealed 926 up- and 439 down-regulated genes in the TSP8-15 ECTCs compared to their healthy counterparts. The application of rapamycin initiated the differential expression of 101 and 31 genes in the CC3 and TSP8-15 ECTCs, respectively. A gene ontology analysis showed that in the CC3 ECTCs, the positive inotropic and chronotropic effects of rapamycin correlated with positively regulated biological processes, which were primarily related to the metabolism of lipids and fatty and amino acids, and with negatively regulated processes, which were predominantly associated with cell proliferation and muscle and tissue development. In conclusion, this study describes for the first time an in vitro TSC cardiac tissue model, illustrates the response of normal and TSC ECTCs to rapamycin, and provides new insights into the mechanisms of TSC.
PubMed: 38534508
DOI: 10.3390/bioengineering11030234