RESUMO
GABAergic interneurons play a critical role in maintaining neural circuit balance, excitation-inhibition regulation, and cognitive function modulation. In tuberous sclerosis complex (TSC), GABAergic neuron dysfunction contributes to disrupted network activity and associated neurological symptoms, assumingly in a cell type-specific manner. This GABAergic centric study focuses on identifying specific interneuron subpopulations within TSC, emphasizing the unique characteristics of medial ganglionic eminence (MGE)- and caudal ganglionic eminence (CGE)-derived interneurons. Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC. The disrupted maturation of SST+ interneurons may undergo an incomplete switch from excitatory to inhibitory GABAergic signaling during development, resulting in reduced inhibitory properties. Notably, this study reveals markers of immaturity specifically in SST+ interneurons, including an abnormal NKCC1/KCC2 ratio, indicating an imbalance in chloride homeostasis crucial for the postsynaptic consequences of GABAergic signaling as well as the downregulation of GABAA receptor subunits, GABRA1, and upregulation of GABRA2. Further exploration of SST+ interneurons revealed altered localization patterns of SST+ interneurons in TSC brain tissue, concentrated in deeper cortical layers, possibly linked to cortical dyslamination. In the epilepsy context, our research underscores the diverse cell type-specific roles of GABAergic interneurons in shaping seizures, advocating for precise therapeutic considerations. Moreover, this study illuminates the potential contribution of SST+ interneurons to TSC pathophysiology, offering insights for targeted therapeutic interventions.
Assuntos
Neurônios GABAérgicos , Interneurônios , Esclerose Tuberosa , Humanos , Neurônios GABAérgicos/patologia , Neurônios GABAérgicos/metabolismo , Eminência Ganglionar , Interneurônios/patologia , Interneurônios/metabolismo , Eminência Mediana/patologia , Eminência Mediana/metabolismo , Receptores de GABA-A/metabolismo , Somatostatina/metabolismo , Esclerose Tuberosa/patologia , Esclerose Tuberosa/metabolismo , AnimaisRESUMO
Tuberous sclerosis complex (TSC) presents with renal cysts and benign tumors, which eventually lead to kidney failure. The factors promoting kidney cyst formation in TSC are poorly understood. Inactivation of carbonic anhydrase 2 (Car2) significantly reduced, whereas, deletion of Foxi1 completely abrogated the cyst burden in Tsc1 KO mice. In these studies, we contrasted the ontogeny of cyst burden in Tsc1/Car2 dKO mice vs. Tsc1/Foxi1 dKO mice. Compared to Tsc1 KO, the Tsc1/Car2 dKO mice showed few small cysts at 47 days of age. However, by 110 days, the kidneys showed frequent and large cysts with overwhelming numbers of A-intercalated cells in their linings. The magnitude of cyst burden in Tsc1/Car2 dKO mice correlated with the expression levels of Foxi1 and was proportional to mTORC1 activation. This is in stark contrast to Tsc1/Foxi1 dKO mice, which showed a remarkable absence of kidney cysts at both 47 and 110 days of age. RNA-seq data pointed to profound upregulation of Foxi1 and kidney-collecting duct-specific H+-ATPase subunits in 110-day-old Tsc1/Car2 dKO mice. We conclude that Car2 inactivation temporarily decreases the kidney cyst burden in Tsc1 KO mice but the cysts increase with advancing age, along with enhanced Foxi1 expression.
Assuntos
Anidrase Carbônica II , Fatores de Transcrição Forkhead , Doenças Renais Císticas , Esclerose Tuberosa , Animais , Camundongos , Anidrase Carbônica II/genética , Anidrase Carbônica II/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Deleção de Genes , Rim/patologia , Rim/metabolismo , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Doenças Renais Císticas/metabolismo , Camundongos Knockout , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Esclerose Tuberosa/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/metabolismoRESUMO
Background: Abnormalities in white matter development may influence development of autism spectrum disorder in tuberous sclerosis complex (TSC). Our goals for this study were as follows: (1) use data from a longitudinal neuroimaging study of tuberous sclerosis complex (TACERN) to develop optimized linear mixed effects models for analyzing longitudinal, repeated diffusion tensor imaging metrics (fractional anisotropy, mean diffusivity) pertaining to select white matter tracts, in relation to positive Autism Diagnostic Observation Schedule-Second Edition classification at 36 months, and (2) perform an exploratory analysis using optimized models applied to all white matter tracts from these data. Methods: Eligible participants (3-12 months) underwent brain magnetic resonance imaging (MRI) at repeated time points from ages 3 to 36 months. Positive Autism Diagnostic Observation Schedule-Second Edition classification at 36 months was used. Linear mixed effects models were fine-tuned separately for fractional anisotropy values (using fractional anisotropy corpus callosum as test outcome) and mean diffusivity values (using mean diffusivity right posterior limb internal capsule as test outcome). Fixed effects included participant age, within-participant longitudinal age, and autism spectrum disorder diagnosis. Results: Analysis included data from n = 78. After selecting separate optimal models for fractional anisotropy and mean diffusivity values, we applied these models to fractional anisotropy and mean diffusivity of all 27 white matter tracts. Fractional anisotropy corpus callosum was related to positive Autism Diagnostic Observation Schedule-Second Edition classification (coefficient = 0.0093, P = .0612), and mean diffusivity right inferior cerebellar peduncle was related to positive Autism Diagnostic Observation Schedule-Second Edition classification (coefficient = -0.00002071, P = .0445), though these findings were not statistically significant after multiple comparisons correction. Conclusion: These optimized linear mixed effects models possibly implicate corpus callosum and cerebellar pathology in development of autism spectrum disorder in tuberous sclerosis complex, but future studies are needed to replicate these findings and explore contributors of heterogeneity in these models.
Assuntos
Transtorno do Espectro Autista , Imagem de Tensor de Difusão , Esclerose Tuberosa , Substância Branca , Humanos , Esclerose Tuberosa/diagnóstico por imagem , Esclerose Tuberosa/complicações , Esclerose Tuberosa/patologia , Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/patologia , Imagem de Tensor de Difusão/métodos , Masculino , Feminino , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Estudos Longitudinais , Pré-Escolar , Lactente , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/crescimento & desenvolvimento , AnisotropiaRESUMO
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 TSC1 or TSC2 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 TSC1/TSC2 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.
Assuntos
Esclerose Tuberosa , Humanos , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Proteína 2 do Complexo Esclerose Tuberosa/genética , Mutação , Testes Genéticos , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
ABSTRACT: Renal hemangioblastoma (HB) is a rare subset of HBs arising outside of the central nervous system (CNS), with its molecular drivers remaining entirely unknown. There were no significant alterations detected in previous studies, including von Hippel-Lindau gene alterations, which are commonly associated with CNS-HB. This study aimed to determine the real molecular identity of renal HB and better understand its relationship with CNS-HB. A cohort of 10 renal HBs was submitted for next-generation sequencing technology. As a control, 5 classic CNS-HBs were similarly analyzed. Based on the molecular results, glycoprotein nonmetastatic B (GPNMB) immunohistochemistry was further performed in the cases of renal HB and CNS-HB. Mutational analysis demonstrated that all 10 renal HBs harbored somatic mutations in tuberous sclerosis complex 1 ( TSC1 , 5 cases), TSC2 (3 cases), and mammalian target of rapamycin (2 cases), with the majority classified as pathogenic or likely pathogenic. The CNS-HB cohort uniformly demonstrated somatic mutations in the von Hippel-Lindau gene. GPNMB was strong and diffuse in all 10 renal HBs and completely negative in CNS-HBs, reinforcing the molecular findings. Our study reveals a specific molecular hallmark in renal HB, characterized by recurrent TSC/mammalian target of rapamycin mutations, which defines it as a unique entity distinct from CNS-HB. This molecular finding potentially expands the therapeutic options for patients with renal HB. GPNMB can be considered for inclusion in immunohistochemical panels to improve renal HB identification.
Assuntos
Hemangioblastoma , Neoplasias Renais , Mutação , Serina-Treonina Quinases TOR , Proteína 2 do Complexo Esclerose Tuberosa , Humanos , Hemangioblastoma/genética , Hemangioblastoma/patologia , Hemangioblastoma/química , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Renais/química , Feminino , Masculino , Proteína 2 do Complexo Esclerose Tuberosa/genética , Adulto , Pessoa de Meia-Idade , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Análise Mutacional de DNA , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/química , Imuno-Histoquímica , Proteína 1 do Complexo Esclerose Tuberosa/genética , Idoso , Predisposição Genética para Doença , Adolescente , Fenótipo , Adulto Jovem , Criança , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
The mediator complex subunit 13 (MED13) gene is implicated in neurodevelopmental disorders including autism spectrum disorder (ASD), intellectual disability, and speech delay with varying severity and course. Additional, extra central nervous system, features include eye or vision problems, hypotonia, congenital heart abnormalities, and dysmorphisms. We describe a 7-year- and 4-month-old girl evaluated for ASD whose brain magnetic resonance imaging was suggestive of multiple cortical tubers. The exome sequencing (ES - trio analysis) uncovered a unique, de novo, frameshift variant in the MED13 gene (c.4880del, D1627Vfs*17), with a truncating effect on the protein. This case report thus expands the phenotypic spectrum of MED13-related disorders to include brain abnormalities.
Assuntos
Transtorno do Espectro Autista , Mutação da Fase de Leitura , Imageamento por Ressonância Magnética , Complexo Mediador , Esclerose Tuberosa , Humanos , Feminino , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/patologia , Transtorno do Espectro Autista/diagnóstico , Complexo Mediador/genética , Mutação da Fase de Leitura/genética , Esclerose Tuberosa/genética , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/diagnóstico por imagem , Esclerose Tuberosa/patologia , Criança , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/anormalidades , Sequenciamento do Exoma , FenótipoRESUMO
Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder characterized by the development of benign tumors in various organs, including the brain, and is often accompanied by epilepsy, neurodevelopmental comorbidities including intellectual disability and autism. A key hallmark of TSC is the hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway, which induces alterations in cortical development and metabolic processes in astrocytes, among other cellular functions. These changes could modulate seizure susceptibility, contributing to the progression of epilepsy and its associated comorbidities. Epilepsy is characterized by dysregulation of calcium (Ca2+) channels and intracellular Ca2+ dynamics. These factors contribute to hyperexcitability, disrupted synaptogenesis, and altered synchronization of neuronal networks, all of which contribute to seizure activity. This study investigates the intricate interplay between altered Ca2+ dynamics, mTOR pathway dysregulation, and cellular metabolism in astrocytes. The transcriptional profile of TSC patients revealed significant alterations in pathways associated with cellular respiration, ER and mitochondria, and Ca2+ regulation. TSC astrocytes exhibited lack of responsiveness to various stimuli, compromised oxygen consumption rate and reserve respiratory capacity underscoring their reduced capacity to react to environmental changes or cellular stress. Furthermore, our study revealed significant reduction of store operated calcium entry (SOCE) along with strong decrease of basal mitochondrial Ca2+ concentration and Ca2+ influx in TSC astrocytes. In addition, we observed alteration in mitochondrial membrane potential, characterized by increased depolarization in TSC astrocytes. Lastly, we provide initial evidence of structural abnormalities in mitochondria within TSC patient-derived astrocytes, suggesting a potential link between disrupted Ca2+ signaling and mitochondrial dysfunction. Our findings underscore the complexity of the relationship between Ca2+ signaling, mitochondria dynamics, apoptosis, and mTOR hyperactivation. Further exploration is required to shed light on the pathophysiology of TSC and on TSC associated neuropsychiatric disorders offering further potential avenues for therapeutic development.
Assuntos
Epilepsia , Esclerose Tuberosa , Humanos , Astrócitos/patologia , Sinalização do Cálcio , Esclerose Tuberosa/patologia , Cálcio/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Epilepsia/genética , Homeostase , ConvulsõesRESUMO
RATIONALE: Tuberous sclerosis complex (TSC) is a rare autosomal dominant inherited disorder characterized by the development of nonmalignant tissue growths (hamartomas) in various organ systems, often located in the brain, skin, heart, lung and kidneys. The delayed diagnosis could be attributed to low expectation or exposure of physicians to this rare disease. High index of clinical suspicion is required for early diagnosis of rare diseases to prevent adverse outcomes. PATIENT CONCERNS: The first patient, a 27-year-old man, presented with intermittent left flank pain and hematuria of 5 months duration. On examination of the skin and oral cavity, he had fibrous cephalic plaque, facial angiofibromas, ungual fibromas, confetti skin lesions, and intraoral fibromas. A CT scan of the chest, abdomen, and brain displayed cystic lung parenchymal changes and multifocal micronodular pneumocyte hyperplasia, angiomyolipomas in both kidneys, and multiple calcified subependymal nodules (SEN), respectively. The second patient, a 28-year-old woman, presented with a seizure disorder in the last 1 year, and papular and nodular lesions over her face since childhood. On examination of the skin and oral cavity, she had hypomelanotic macules, facial angiofibromas, shagreen patches, ungual fibromas, intraoral fibromas, and dental enamel pits. DIAGNOSES: Definitive diagnosis of TSC was made in both patients using the "2012 tuberous sclerosis complex diagnostic criteria consensus statement." INTERVENTIONS: The first patient was seen by various medical discipline teams, and suggested close follow-up in the "chronic illness clinic" of the hospital. The second patient was scheduled in dermatology clinic for electrocautery for disfiguring facial nodules. OUTCOME: Both patients were scheduled for close follow-up in the hospital. LESSONS: The patients described had TSC using "clinical diagnostic criteria." Under the clinical diagnostic criteria of TSC, 4 of 11 major criteria and 3 of 7 minor criteria are skin features. Hence, awareness on skin features as clinical markers to suspect TSC should be emphasized in resource-limited countries.
Assuntos
Angiofibroma , Fibroma , Hamartoma , Dermatopatias , Esclerose Tuberosa , Adulto , Feminino , Humanos , Masculino , Angiofibroma/patologia , Fibroma/patologia , Hamartoma/patologia , Hiperplasia/patologia , Pele/patologia , Dermatopatias/diagnóstico , Esclerose Tuberosa/complicações , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/patologiaAssuntos
Hemangioblastoma , Neoplasias Pancreáticas , Esclerose Tuberosa , Humanos , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/complicações , Hemangioblastoma/cirurgia , Hemangioblastoma/complicações , Hemangioblastoma/patologia , Esclerose Tuberosa/complicações , Esclerose Tuberosa/patologia , Feminino , Adulto , Tomografia Computadorizada por Raios X , MasculinoRESUMO
BACKGROUND/AIM: Tuberous sclerosis complex (TSC) is a multi-system syndrome caused by loss-of-function mutation in TSC1 or TSC2. Most TSC patients present with cardiac rhabdomyoma or cortical tubers during fetal life, and the symptoms are not uniform as their age. The gene products of TSC1/2 are components of the TSC protein complex and are important role in the PI3K/AKT/mTOR (PAM) signaling pathway. Based on three members of a family with variable expressivity, the purpose of this study was to clarify the clinical features of TSC in different age groups and to analyze the genetic characteristics of TSC2 gene. METHODS: Clinical exome sequencing and co-segregation were used to identify a three-generation family with four affected individuals. HEK-293T cell model was constructed for subsequent experiments. Quantitative RT-PCR, western blotting, and subcellular localization were used to analyze the expression effect of TSC2 mutation. CCK-8 assay, wound healing assay, and cell cycle analysis were used to analyze the function effect of TSC2 mutation. RESULT: We identified a TSC family with heterozygous deletion of exon 4 in TSC2 by clinical exon sequencing. Sanger sequencing indicated that the affected individuals have 2541-bp deletion that encompassed exon 4 and adjacent introns. Deletion of exon 4 decreased the TSC2 mRNA and protein levels in HEK-293T cells, and activated the PI3K/AKT/mTOR pathway, thereby altering the cell cycle and promoting cell proliferation and migration. CONCLUSION: We confirmed the pathogenicity of the large deletion in TSC2 in a three- generations family.. Deletion of exon 4 of TSC2 affected cell proliferation, migration, and cell cycle via abnormal activation of the PAM pathway. This study evaluated the pathogenic effect of deletion of exon 4 of TSC2 and investigated the underlying mechanism.
Assuntos
Esclerose Tuberosa , Proteínas Supressoras de Tumor , Humanos , Mutação , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type IIb are the predominant causes of drug-refractory epilepsy in children. Dysmorphic neurons (DNs), giant cells (GCs), and balloon cells (BCs) are the most typical pathogenic profiles in cortical lesions of TSC and FCD IIb patients. However, mechanisms underlying the pathological processes of TSC and FCD IIb remain obscure. The Plexin-B2-Sema4C signalling pathway plays critical roles in neuronal morphogenesis and corticogenesis during the development of the central nervous system. However, the role of the Plexin-B2 system in the pathogenic process of TSC and FCD IIb has not been identified. In the present study, we investigated the expression and cell distribution characteristics of Plexin-B2 and Sema4C in TSC and FCD IIb lesions with molecular technologies. Our results showed that the mRNA and protein levels of Plexin-B2 expression were significantly increased both in TSC and FCD IIb lesions versus that in the control cortex. Notably, Plexin-B2 was also predominantly observed in GCs in TSC epileptic lesions and BCs in FCD IIb lesions. In contrast, the expression of Sema4C, the ligand of Plexin-B2, was significantly decreased in DNs, GCs, and BCs in TSC and FCD IIb epileptic lesions. Additionally, Plexin-B2 and Sema4C were expressed in astrocytes and microglia cells in TSC and FCD IIb lesions. Furthermore, the expression of Plexin-B2 was positively correlated with seizure frequency in TSC and FCD IIb patients. In conclusion, our results showed the Plexin-B2-Sema4C system was abnormally expressed in cortical lesions of TSC and FCD IIb patients, signifying that the Plexin-B2-Sema4C system may play a role in the pathogenic development of TSC and FCD IIb.
Assuntos
Displasia Cortical Focal , Malformações do Desenvolvimento Cortical do Grupo I , Proteínas do Tecido Nervoso , Semaforinas , Esclerose Tuberosa , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Epilepsia Resistente a Medicamentos/metabolismo , Epilepsia Resistente a Medicamentos/patologia , Epilepsia , Displasia Cortical Focal/metabolismo , Displasia Cortical Focal/patologia , Células Gigantes/metabolismo , Células Gigantes/patologia , Malformações do Desenvolvimento Cortical do Grupo I/metabolismo , Malformações do Desenvolvimento Cortical do Grupo I/patologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Neurônios/metabolismo , Neurônios/patologia , Semaforinas/metabolismo , Semaforinas/genética , Semaforinas/biossíntese , Esclerose Tuberosa/metabolismo , Esclerose Tuberosa/patologiaRESUMO
Tuberous sclerosis complex (TSC) is a genetic disease that causes benign tumors and dysfunctions in many organs, including the brain. Aside from the brain malformations, many individuals with TSC exhibit neuropsychiatric symptoms. Among these symptoms, autism spectrum disorder (ASD) is one of the most common co-morbidities, affecting up to 60% of the population. Past neuroimaging studies strongly suggested that the impairments in brain connectivity contribute to ASD, whether or not TSC-related. Specifically, the tract-based diffusion tensor imaging (DTI) analysis provides information on the fiber integrity and has been used to study the neuropathological changes in the white matter of TSC patients with ASD symptoms. In our previous study, curcumin, a diet-derived mTOR inhibitor has been shown to effectively mitigate learning and memory deficits and anxiety-like behavior in Tsc2+/- mice via inhibiting astroglial proliferation. Recently, gut microbiota, which is greatly influenced by the diet, has been considered to play an important role in regulating several components of the central nervous system, including glial functions. In this study, we showed that the abnormal social behavior in the Tsc2+/- mice can be ameliorated by the dietary curcumin treatment. Second, using tract-based DTI analysis, we found that the Tsc2+/- mice exhibited altered fractional anisotropy, axial and radial diffusivities of axonal bundles connecting the prefrontal cortex, nucleus accumbens, hypothalamus, and amygdala, indicating a decreased brain network. Third, the dietary curcumin treatment improved the DTI metrics, in accordance with changes in the gut microbiota composition. At the bacterial phylum level, we showed that the abundances of Actinobacteria, Verrucomicrobia, and Tenericutes were significantly correlated with the DTI metrics FA, AD, and RD, respectively. Finally, we revealed that the expression of myelin-associated proteins, myelin bassic protein (MBP) and proteolipid protein (PLP) was increased after the treatment. Overall, we showed a strong correlation between structural connectivity alterations and social behavioral deficits, as well as the diet-dependent changes in gut microbiota composition.
Assuntos
Transtorno do Espectro Autista , Curcumina , Microbioma Gastrointestinal , Esclerose Tuberosa , Humanos , Camundongos , Animais , Imagem de Tensor de Difusão/métodos , Esclerose Tuberosa/diagnóstico por imagem , Esclerose Tuberosa/complicações , Esclerose Tuberosa/patologia , Curcumina/farmacologia , EncéfaloRESUMO
BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder, caused by a loss-of-function of either TSC1 or TSC2 gene. However, in 10%-15% TSC patients there is no pathogenic variant identified in either TSC1 or TSC2 genes based on standard clinical testing. METHODS: In this study, genome sequencing was performed for families with clinical diagnosis of TSC with negative results from TSC1 and TSC2 single-gene tests. RESULTS: Herein, we report a family presenting a classical TSC phenotype with an unusual, complex structural variant involving the TSC1 gene: an intrachromosomal inverted insertion in the long arm of chromosome 9. We speculate that the inverted 9q33.3q34.13 region was inserted into the q31.2 region with the 3'-end of the breakpoint of the inversion being located within the TSC1 gene, resulting in premature termination of TSC1. CONCLUSIONS: In this study, we demonstrate the utility of genome sequencing for the identification of complex chromosomal rearrangement. Because the breakpoints are located within the deep intronic/intergenic region, this copy-neutral variant was missed by the TSC1 and TSC2 single-gene tests and contributed to an unknown etiology. Together, this finding suggests that complex structural variants may be underestimated causes for the etiology of TSC.
Assuntos
Esclerose Tuberosa , Proteínas Supressoras de Tumor , Humanos , Proteínas Supressoras de Tumor/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Mutação , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Cromossomos Humanos Par 9 , República da CoreiaRESUMO
OBJECTIVE: This article assesses the efficacy, safety, pharmacology, and clinical applications of topical sirolimus 0.2% gel for the treatment of tuberous sclerosis complex (TSC)-associated facial angiofibromas. DATA SOURCES: A review of the literature was conducted using the Medline (PubMed) and EMBASE databases using the keywords topical sirolimus, rapamycin, Hyftor, and tuberous sclerosis. STUDY SELECTION AND DATA EXTRACTION: Articles written in English and relevant to the topic were included. DATA SYNTHESIS: In the phase 2 trial, the mean improvement factor, a composite measure of improved tumor size and redness, was achieved in all patient groups (P < 0.001) with significant responses among the adult and pediatric subgroups at week 12. There were no serious adverse events recorded. In the phase 3 trial, 60% of participants responded to treatment in the sirolimus group compared with 0% in the placebo group with different response rates between the adult and pediatric subgroups at week 12. Sirolimus gel had no serious adverse events, and dry skin was the most common adverse reaction. Patients who had completed the 12-week trials were then enrolled in a long-term trial; angiofibromas had response rates of 78.2% to 0.2% sirolimus gel. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS: Topical sirolimus 0.2% is a first-in-class, newly Food and Drug Administration (FDA)-approved, mammalian target of rapamycin (mTOR) inhibitor that is a promising and safe, noninvasive alternative to surgical procedures for TSC-associated angiofibromas. CONCLUSIONS: Topical sirolimus 0.2% gel is a moderately effective treatment for TSC-associated facial angiofibromas with an adequate safety profile.
Assuntos
Angiofibroma , Neoplasias Faciais , Esclerose Tuberosa , Adulto , Humanos , Criança , Esclerose Tuberosa/complicações , Esclerose Tuberosa/tratamento farmacológico , Esclerose Tuberosa/patologia , Angiofibroma/tratamento farmacológico , Angiofibroma/etiologia , Neoplasias Faciais/etiologia , Neoplasias Faciais/induzido quimicamente , Imunossupressores , Sirolimo/efeitos adversos , Géis/uso terapêuticoRESUMO
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease characterized by hamartomatous tumors involving multiple organs such as the brain, skin, heart, lung and kidney. TSC is caused by inactivating mutations in TSC1/TSC2, which encodes hamartin and tuberin, respectively, and forms a complex that regulates mechanistic target of rapamycin complex 1 (mTORC1), resulting in cell overgrowth and oncogenesis. Since a leading cause of morbidity and mortality in TSC relates to chronic kidney disease and the ability to preserve renal function, this review describes the important pathologic findings in TSC-associated renal neoplasms and their correlating sporadic counterparts. The most common renal tumor in TSC patients are AMLs, followed by a heterogeneous spectrum of renal epithelial tumors, which may provide clues to establishing a diagnosis of TSC.
Assuntos
Carcinoma de Células Renais , Hamartoma , Neoplasias Renais , Esclerose Tuberosa , Humanos , Carcinoma de Células Renais/genética , Esclerose Tuberosa/genética , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Rim/patologiaRESUMO
ABSTRACT: Subependymal giant cell astrocytomas (SEGAs) are low-grade gliomas usually arising in the periventricular regions near the foramen of Monro seen exclusively with tuberous sclerosis complex. Incidence of hemorrhage in SEGA is less than 1% with only 10 cases reported in English literature. We present a similar case of SEGA with spontaneous intratumoral hemorrhage in a 35-year-old male with cutaneous manifestations of tuberous sclerosis complex and acute onset headache with convulsion.
Assuntos
Astrocitoma , Neoplasias Encefálicas , Humanos , Masculino , Adulto , Astrocitoma/complicações , Astrocitoma/patologia , Astrocitoma/diagnóstico , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/patologia , Hemorragia/etiologia , Hemorragia/patologia , Hemorragia/diagnóstico , Imageamento por Ressonância Magnética , Esclerose Tuberosa/complicações , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/patologiaRESUMO
BACKGROUND: Despite its rare incidence of 1/40,000, fetal cardiac rhabdomyoma (CR) represents the prevailing type of benign cardiac fetal tumors, which commonly affects the ventricles. Fetal CRs rarely occur in the right atrium. Thus, the presentation of atrial fibrillation and premature atrial contractions (PAC) due to a solitary cardiac rhabdomyoma is an extremely rare scenario. Our literature review found that only 2% (1 out of 61) of rhabdomyoma cases were found in the right atrium. The majority of fetal cardiac rhabdomyomas are associated with tuberous sclerosis complex (TSC). CASE PRESENTATION: A 7-day-old male neonate presented with arrhythmias and an atrial mass for further evaluation. Echocardiography revealed a hyperechoic, round, uniform right atrial mass (25 mm). An abdominal and testicular ultrasound showed multiple thin-walled cortical cysts in both kidneys and a scrotal hydrocele, respectively. His laboratory workup was insignificant except for hypomagnesemia. Electrocardiography revealed junctional rhythm and PACs with wave distortions. A brain magnetic resonance imaging scan revealed multiple subependymal lesions on the frontal and occipital horns of the lateral ventricles. These findings (Fig. 1), along with a family history of TSC, confirmed the diagnosis of TSC with associated CR. The patient was treated symptomatically with an anti-convulsant and monitored with regular follow-ups. Surgical resection was not required. CONCLUSION: Despite CR's predominance in the ventricles, a diagnosis of rhabdomyoma should be kept in mind in the presence of a solitary atrial mass and PACs. Physicians should evaluate systemic findings related to TSC and provide appropriate follow-up and family screening. Surgical resection is not always required, and symptom management can be achieved through medical treatment alone.
Assuntos
Neoplasias Cardíacas , Rabdomioma , Esclerose Tuberosa , Lactente , Recém-Nascido , Humanos , Masculino , Esclerose Tuberosa/complicações , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/patologia , Rabdomioma/complicações , Rabdomioma/diagnóstico por imagem , Ecocardiografia/métodos , Eletrocardiografia , Átrios do Coração , Arritmias Cardíacas/complicações , Neoplasias Cardíacas/complicações , Neoplasias Cardíacas/diagnóstico por imagem , Neoplasias Cardíacas/cirurgiaRESUMO
The occurrence of central nervous system malignancies is relatively low; however, these tumors exhibit poor prognosis and a high mortality rate. On epidemiological grounds, Hungary was placed in the last third among European countries: in the last decade annually 750 to 1000 new cases were diagnosed and the number of deaths was between 550 and 690, without any apparent trends. Age distribution analyses revealed childhood peak and a higher peak at around 65 years of age. Histologically, heterogeneity was apparent, but at least half of the cases were glioblastomas. The exact etiology of adulthood brain tumors is mostly unknown. Among environmental exposures the effect of ionizing radiation was confirmed, the identification of other potential risk factors requires further examinations. 7-10 percent of brain tumors were hereditary tumor syndromes (Li-Fraumeni, neurofibromatosis, sclerosis tuberosa, von Hippel-Lindau, Gorlin- Goltz). Therefore, genetic testing is recommended for families where the diagnosis of brain tumor is suspected.
Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Síndromes Neoplásicas Hereditárias , Esclerose Tuberosa , Doença de von Hippel-Lindau , Humanos , Adulto , Criança , Idoso , Doença de von Hippel-Lindau/diagnóstico , Doença de von Hippel-Lindau/epidemiologia , Doença de von Hippel-Lindau/patologia , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Esclerose Tuberosa/epidemiologia , Esclerose Tuberosa/patologiaRESUMO
GENOTYPE/PHENOTYPE CORRELATIONS IN TUBEROUS SCLEROSIS COMPLEX: Paolo Curatolo MD, Romina Moavero MD, Denis Roberto, Federica Graziola Seminars in Pediatric Neurology Volume 22, Issue 4, December 2015, Pages 259-273 Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of widespread hamartomatous lesions in various organs, including brain, skin, kidneys, heart, and eyes. Central nervous system is almost invariably involved, with up to 85% of patients presenting with epilepsy, and at least half of patients having intellectual disability or other neuropsychiatric disorders including autism spectrum disorder. TSC is caused by the mutation in one of the 2 genes TSC1, at 9q34, and TSC2, at 16p13.3. They respectively encode for hamartin and tuberin, which form an intracellular complex inhibiting the mammalian target of rapamycin. Mammalian target of rapamycin overactivation following the genetic defect determines the cell growth and proliferation responsible for TSC-related lesions, as well as the alterations in neuronal excitability and synaptogenesis leading to epilepsy and neuropsychiatric disorders. A causative mutation for the disorder is identified in about 85% of patients with a clinical diagnosis of TSC. Mosaicism and technology limits likely explain most of the no mutation identified cases. This review confirms that patients with TSC2 mutations considered as a group usually present a more severe phenotype, characterized by higher number of tubers, earlier age at seizure onset and higher prevalence of intellectual disability. However, the clinical phenotype of the disease presents a high variability, thus making the prediction of the phenotype on an individual basis still challenging. The increasing application of new molecular techniques to subjects with TSC has the potential to significantly reduce the rate of patients with no mutation demonstrated and to identify an increasing higher number of mutations. This would hopefully allow a better characterization of higher risk mutations, which might help clinicians to plan individualized surveillance plans. Furthermore, the increasing availability of disease registries to collect clinical and genetics data of patients help to define more valid and clinically oriented genotype or phenotype correlations.
Assuntos
Transtorno do Espectro Autista , Epilepsia , Deficiência Intelectual , Esclerose Tuberosa , Criança , Humanos , Proteínas Supressoras de Tumor/genética , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Mutação , Epilepsia/genética , Estudos de Associação Genética , Serina-Treonina Quinases TOR/genéticaRESUMO
BACKGROUND: Tuberous sclerosis complex (TSC) is a rare genetic disease that affects multiple organs and affects the quality of life. Mutations in TSC1 and TSC2 genes are causing dysregulations in the mammalian target of the rapamycin (mTOR) pathway, inducing mostly benign but also malignant tumors, including renal cell carcinoma (RCC). The diagnosis of TSC, based on established clinical and genetic criteria, is essential for the optimal surveillance and management of patients. CASE PRESENTATION: With the current report, we present the case of two sisters who were consequently diagnosed with early-stage chromophobe-like RCC, possibly familial given their young age. The younger sister also had a previous diagnosis of differentiated thyroid carcinoma, for which she had been treated properly. Genetic testing of both revealed the same heterozygous TSC2 variant that is currently regarded as a variant of unknown significance, while both patients did not fulfill the clinical criteria for the diagnosis of TSC. Owing to these data, we opted to manage and surveil both sisters as TSC patients, while we also considered the specific TSC2 variant to be pathogenic - but of low penetrance - based on clinical judgment and functional analyses. Furthermore, we discussed the implementation of mTOR inhibitors for the treatment of TSC complications. CONCLUSION: As novel pathogenic variants of TSC genes are constantly being explored, the identification of TSC variants of unknown significance in combination with absent clinical diagnostic criteria cannot exclude a TSC diagnosis. We support the implementation of clinical judgment in assisting the diagnosis of TSC, as well as the enrollment of patients in clinical trials due to the rarity of the disease.