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Tuberous Sclerosis Complex (tuberous + sclerosis_complex)
Selected AbstractsMechanisms of Epileptogenesis in Tuberous Sclerosis Complex and Related Malformations of Cortical Development with Abnormal Glioneuronal ProliferationEPILEPSIA, Issue 1 2008Michael Wong Summary Malformations of cortical development (MCDs) are increasingly recognized as causes of medically intractable epilepsy. In order to develop more effective, rational therapies for refractory epilepsy related to MCDs, it is important to achieve a better understanding of the underlying mechanisms of epileptogenesis, but this is complicated by the wide variety of different radiographic, histopathological, and molecular features of these disorders. A subset of MCDs share a number of characteristic cellular and molecular abnormalities due to early defects in neuronal and glial proliferation and differentiation and have a particularly high incidence of epilepsy, suggesting that this category of MCDs with abnormal glioneuronal proliferation may also share a common set of primary mechanisms of epileptogenesis. This review critically analyzes both clinical and basic science evidence for overlapping mechanisms of epileptogenesis in this group of disorders, focusing on tuberous sclerosis complex, focal cortical dysplasia with balloon cells, and gangliogliomas. Specifically, the role of lesional versus perilesional regions, circuit versus cellular/molecular defects, and nonneuronal factors, such as astrocytes, in contributing to epileptogenesis in these MCDs is examined. An improved understanding of these various factors involved in epileptogenesis has direct clinical implications for optimizing current treatments or developing novel therapeutic approaches for epilepsy in these disorders. [source] Treatment before Seizures: New Indications for Antiepileptic Therapy in Children with Tuberous Sclerosis ComplexEPILEPSIA, Issue 8 2007Sergiusz Józwiak No abstract is available for this article. [source] Can Preventative Antiepileptic Therapy Alter Outcome in Infants with Tuberous Sclerosis Complex?EPILEPSIA, Issue 8 2007Carl E. Stafstrom No abstract is available for this article. [source] Consistent Localization of Interictal Epileptiform Activity on EEGs of Patients with Tuberous Sclerosis ComplexEPILEPSIA, Issue 3 2005Floor E. Jansen Summary:,Purpose: We addressed consistent localization of focal interictal epileptiform activity on EEGs of patients with tuberous sclerosis complex (TSC) and epilepsy. Methods: Twenty-one patients with TSC with a 10-year history of epilepsy and interictal epileptiform activity in three or more EEG recordings were included. None of the patients had undergone epilepsy surgery. Local maxima of interictal epileptiform activity were measured from 76 EEG traces and 33 EEG reports. Information about the patients' clinical course was extracted from their medical records. Magnetic resonance imaging (MRI) and neuropsychological examinations were performed. Statistical analysis was performed with the Mann,Whitney U test. Results: In eight patients, interictal epileptiform activity was consistently detected in one or two regions (group 1), and in 13 patients, epileptiform activity was detected in three or more regions (group 2). The number of foci increased throughout the disease course in both groups. Age at seizure onset and IQ were significantly higher in group 1. Complex partial seizures occurred more often in the patients of group 1. In 19 of the 21 patients, the most consistent epileptiform activity was localized in the frontotemporal region. Conclusions: Ninety percent of patients with TSC showed at least one region of consistent interictal epileptiform activity. Patients with one or two regions of epileptiform activity were older at seizure onset, often experienced complex partial seizures, and had mild or no mental deficits. These patients may be candidates for epilepsy surgery. [source] What can we learn from tuberous sclerosis complex (TSC) about autism?JOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 10 2008P. J. De Vries Tuberous Sclerosis Complex (TSC) is now recognized as one of the medical conditions most commonly associated with autism. Between 1,5% of those with autism have TSC and up to 50% of people with TSC meet criteria for an autism spectrum disorder. The clinical characteristics of autism in TSC are qualitatively indistinguishable from those of idiopathic autism. So, what can TSC teach us about autism? We will present an overview of the neuropsychiatric features of TSC and will proceed with an examination of aetiological models of autism in TSC. Structural models (suggesting that autism is caused by brain lesions in specific neuroanatomical locations) and seizure models (suggesting that the age, type and control of seizures may predict autism) have both received some support, but with limited replication. More recently, molecular approaches have suggested that dysregulation of intracellular signalling through the TSC1/2-mTOR pathway may be sufficient to lead to socialization deficits and autism, and that drugs that act as mTOR inhibitors may reverse some aspects of the learning and social deficits in TSC. [source] Distinct clinical characteristics of Tuberous Sclerosis Complex patients with no mutation identifiedANNALS OF HUMAN GENETICS, Issue 2 2009S. E. Camposano Summary Tuberous Sclerosis Complex (TSC) is a multi-system disorder that is highly variable in its clinical presentation. Current molecular diagnostic methods permit identification of mutations in either TSC1 or TSC2 in 75,85% of TSC patients. Here we examine the clinical characteristics of those TSC patients who have no mutation identified (NMI). A retrospective review of our patient population that had comprehensive testing for mutations in TSC1/TSC2 identified 23/157 (15%) that were NMI. NMI patients had a lower incidence of brain findings on imaging studies, neurological features, and renal findings than those with TSC2 mutations. In contrast, NMI patients had a lower incidence of seizures than TSC patients with TSC1 mutations, but had a higher incidence of both renal angiomyolipomas and pulmonary lymphangioleiomyomatosis. This distinct constellation of findings suggest that NMI patients may have a unique molecular pathogenesis, different from that seen in TSC patients with the usual mutations in TSC1 and TSC2. We suggest that the mechanisms of disease in these patients include both mosaicism for a TSC2 mutation, and unusual non-coding region mutations in TSC2. [source] Abnormal giant cells in the cerebral lesions of tuberous sclerosis complexCONGENITAL ANOMALIES, Issue 1 2007Masashi Mizuguchi ABSTRACT Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations of either of the two tumor suppressor genes, TSC1 and TSC2, encoding hamartin and tuberin, respectively. TSC is pathologically characterized by the occurrence of multiple hamartias (focal dysplasias) and hamartomas (benign tumors) in the brain and many other organs. Cortical tubers are hamartias in the cerebral cortex responsible for many neuropsychiatric symptoms of TSC. Unlike TSC-associated hamartomas, cortical tubers do not result from second somatic mutations of the TSC gene, and the mechanism by which they occur remains obscure. Histologically, the most conspicuous feature of cortical tubers is the presence of abnormal giant cells, which show abnormal size and differentiation. Recent studies on human TSC and its animal models have elucidated the critical roles of hamartin and tuberin regulating the growth and differentiation of neural cells. [source] Role of the Rap1 GTPase in astrocyte growth regulationGLIA, Issue 3 2003Anthony J. Apicelli Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome in which affected individuals develop nervous system abnormalities that might reflect astrocyte dysfunction. The TSC2 gene product, tuberin, encodes a GTPase-activating protein (GAP) domain, which regulates the activity of Rap1 in vitro. To determine whether dysregulated Rap1, resulting from TSC2 inactivation, leads to increased astrocyte proliferation in vivo, we generated transgenic mice expressing activated Rap1G12V specifically in astrocytes. We observed no statistically significant difference in the number of astrocytes between wild-type and GFAP-Rap1G12V littermates in vivo; however, during log-phase growth, we observed a 25% increase in GFAP-Rap1G12V astrocyte doubling times compared to wild-type controls. This decreased proliferation was associated with delayed MAP kinase, but not AKT, activation. Lastly, to determine whether constitutive Rap1 activation could reverse the increased astrocyte proliferation observed in transgenic mice expressing oncogenic RasG12V, we generated transgenic mice expressing both RasG12V and Rap1G12V in astrocytes. These double transgenic mice showed a striking reversion of the RasG12V astrocyte growth phenotype. Collectively, these results argue that the tumor suppressor properties of tuberin are unlikely to be related to Rap1 inactivation and that Rap1 inhibits mitogenic Ras pathway signaling in astrocytes. GLIA 42:225,234, 2003. © 2003 Wiley-Liss, Inc. [source] Overexpression of MLH-1 and psoriasin genes in cutaneous angiofibromas from tuberous sclerosis complex patientsJOURNAL OF CUTANEOUS PATHOLOGY, Issue 9 2006Michelangelo La Placa Background:, Tuberous sclerosis complex (TSC) is associated with mutations in two likely tumor-suppressor genes (TSC1 and TSC2) and characterized by the development of tumor-like growths (angiofibromas) in a variety of tissues and organs, particularly brain and skin. Methods:, Employing a DNA-microarray assay, able to detect mRNA production from 1176 different basic genes, we analyzed the gene-expression levels in a cutaneous hamartoma sample from a TSC patient. Altered gene expressions detected by microarray technology were further checked by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) in the same material and in cutaneous hamartoma samples obtained from five other TSC patients. Results:, The results obtained by the microarray technology in one hamartoma specimen, confirmed by the RT-PCR results obtained in the same material and in five other hamartoma specimens, demonstrated that TSC-related angiofibromas exhibit significant mRNA overexpression of two genes, represented by MLH-1 and psoriasin. Conclusions:, The overexpression of MLH-1, which codes for a DNA mismatch repair protein, and psoriasin, which codes for a specific chemoattractant factor for CD4+ T cells, implicated in the pathogenesis of inflammatory skin disease, and expressed in excess during abnormal pathways of cell growth, may shed light on the pathogenesis of the proliferative skin lesion. [source] Clinicopathological and immunohistochemical findings in an autopsy case of tuberous sclerosis complexNEUROPATHOLOGY, Issue 6 2008Karin Boer Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder caused by mutations in either the TSC1 or TSC2 genes and characterized by developmental brain abnormalities. In the present study we discuss the neuropathological findings of a 32-year-old patient with a germ-line mutation in the TSC2 gene. Post mortem MRI combined with histology and immunocytochemical analysis was applied to demonstrate widespread anatomical abnormalities of gray and white matter structure. TSC brain lesions were analyzed for loss of heterozygosity (LOH) on chromosome 16p13. The neuropathological supratentorial abnormalities were represented by multiple subependymal nodules (SENs) and cortical tubers. In addition to cerebral cortical lesions, cerebellar lesions and hippocampal sclerosis were also observed. LOH was not found in the cortical tubers and SENs of this patient. Immunocytochemical analysis of the TSC brain lesions confirmed the cell-specific activation of the mTOR pathway in cortical tubers, SENs and cerebellum, as well as differential cellular localization of hamartin and tuberin, the TSC1 and TSC2 gene products. Examination of the pathological brain regions revealed activated microglial cells and disruption of blood-brain barrier permeability. Predominant intralesional cell-specific distribution was also detected for the multidrug transporter protein P-gp, possibly explaining the mechanisms underlying the pharmacoresistance to antiepileptic drugs. Autopsy findings confirm the complexity of the brain abnormalities encountered in TSC patients and proved useful in clarifying certain aspects of the pathogenesis, epileptogenesis and pharmacoresistance of TSC lesions. [source] Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complexANNALS OF NEUROLOGY, Issue 4 2008Ling-Hui Zeng MD Objective Tuberous sclerosis complex (TSC) represents one of the most common genetic causes of epilepsy. TSC gene inactivation leads to hyperactivation of the mammalian target of rapamycin signaling pathway, raising the intriguing possibility that mammalian target of rapamycin inhibitors might be effective in preventing or treating epilepsy in patients with TSC. Mice with conditional inactivation of the Tsc1 gene primarily in glia (Tsc1GFAPCKO mice) develop glial proliferation, progressive epilepsy, and premature death. Here, we tested whether rapamycin could prevent or reverse epilepsy, as well as other cellular and molecular brain abnormalities in Tsc1GFAPCKO mice. Methods Tsc1GFAPCKO mice and littermate control animals were treated with rapamycin or vehicle starting at postnatal day 14 (early treatment) or 6 weeks of age (late treatment), corresponding to times before and after onset of neurological abnormalities in Tsc1GFAPCKO mice. Mice were monitored for seizures by serial video-electroencephalogram and for long-term survival. Brains were examined histologically for astrogliosis and neuronal organization. Expression of phospho-S6 and other molecular markers correlating with epileptogenesis was measured by Western blotting. Results Early treatment with rapamycin prevented the development of epilepsy and premature death observed in vehicle-treated Tsc1GFAPCKO mice. Late treatment with rapamycin suppressed seizures and prolonged survival in Tsc1GFAPCKO mice that had already developed epilepsy. Correspondingly, rapamycin inhibited the abnormal activation of the mammalian target of rapamycin pathway, astrogliosis, and neuronal disorganization, and increased brain size in Tsc1GFAPCKO mice. Interpretation Rapamycin has strong efficacy for preventing seizures and prolonging survival in Tsc1GFAPCKO mice. Ann Neurol 2008 [source] Cognitive deficits in Tsc1+/,mice in the absence of cerebral lesions and seizuresANNALS OF NEUROLOGY, Issue 6 2007Susanna M. I. Goorden MSc Objective Tuberous sclerosis complex (TSC) is characterized by brain lesions, epilepsy, increased incidence of mental retardation and autism. The causal link between lesion load and epilepsy on cognitive disabilities has been debated, and these factors explain only part of the intelligence quotient variability. A Tsc2 rat model of the disease provided evidence that the TSC genes are directly involved in neuronal function. However, these lesion- and epilepsy-free animals did not show learning deficits, leaving open the possibility that the presence of brain lesions or epilepsy is a prerequisite for the cognitive deficits to fully develop. Here, we reinvestigated the relation among cerebral lesions, epilepsy, and cognitive function using Tsc1+/,mice. Methods We used immunocytochemistry and high-resolution magnetic resonance imaging to study the presence of neuronal pathology in Tsc1+/,mice. We used the Morris water maze, fear conditioning, social interaction, and nest building test to study the presence of cognitive and social deficits. Results We observed no spontaneous seizures or cerebral lesions in the brains of Tsc1+/,mice. In addition, giant dysmorphic cells were absent, and spine number and dendritic branching appeared to be normal. Nevertheless, Tsc1+/,mice showed impaired learning in the hippocampus-sensitive versions of the learning tasks and impaired social behavior. Interpretation Tsc1+/,mice show social and cognitive deficits in the absence of apparent cerebral pathology and spontaneous seizures. These findings support a model in which haploinsufficiency for the TSC genes leads to aberrations in neuronal functioning resulting in impaired learning and social behavior. Ann Neurol 2007 [source] Tuberous sclerosis complex and myocardial fat-containing lesions: a report of four casesCLINICAL GENETICS, Issue 4 2007EB Winterkorn MD No abstract is available for this article. [source] Abnormal giant cells in the cerebral lesions of tuberous sclerosis complexCONGENITAL ANOMALIES, Issue 1 2007Masashi Mizuguchi ABSTRACT Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations of either of the two tumor suppressor genes, TSC1 and TSC2, encoding hamartin and tuberin, respectively. TSC is pathologically characterized by the occurrence of multiple hamartias (focal dysplasias) and hamartomas (benign tumors) in the brain and many other organs. Cortical tubers are hamartias in the cerebral cortex responsible for many neuropsychiatric symptoms of TSC. Unlike TSC-associated hamartomas, cortical tubers do not result from second somatic mutations of the TSC gene, and the mechanism by which they occur remains obscure. Histologically, the most conspicuous feature of cortical tubers is the presence of abnormal giant cells, which show abnormal size and differentiation. Recent studies on human TSC and its animal models have elucidated the critical roles of hamartin and tuberin regulating the growth and differentiation of neural cells. [source] Evaluation of epileptogenic networks in children with tuberous sclerosis complex using EEG-fMRIEPILEPSIA, Issue 5 2008Julia Jacobs Summary Purpose: Ninety percent of patients with tuberous sclerosis complex (TSC) have epilepsy. Identification of epileptogenic areas can be difficult and studies are needed to characterize the epileptogenic network in more detail. Methods: Five children with TSC and focal epilepsy were studied using simultaneous EEG and functional MRI recordings. Tubers were marked by a neuroradiologist on the anatomical MRI. Spike-associated BOLD (blood oxygenation level-dependent) responses were superimposed with lesions. Results: Thirteen different types of interictal epileptiform discharges (IED) were analyzed with 12 showing a BOLD response, all involving more than one tuber. Five studies had tubers with activations exclusively within the lesion, three studies had lesional activations extending to perilesional areas, and two studies had activations involving exclusively perilesional areas of at least one tuber. Deactivations exclusively within a tuber were found in six studies, lesional deactivations extending to perilesional areas were found in four studies, and tubers with exclusively perilesional deactivations were found in five studies. A BOLD response was found in at least one tuber in the lobe of IED generation and presumed seizure onset (according to telemetry) in all patients. In four patients, the same tubers were involved following different IED localizations. The observed changes were always multifocal, sometimes involving tubers distant from the IED field. Discussion: These findings suggest extended epileptogenic networks in patients with TSC, which exceed networks described in PET and SPECT studies. It was possible to identify specific interictally active tubers. EEG-fMRI provides a noninvasive method to select tubers and areas at their borders for further presurgical investigations. [source] Mechanisms of Epileptogenesis in Tuberous Sclerosis Complex and Related Malformations of Cortical Development with Abnormal Glioneuronal ProliferationEPILEPSIA, Issue 1 2008Michael Wong Summary Malformations of cortical development (MCDs) are increasingly recognized as causes of medically intractable epilepsy. In order to develop more effective, rational therapies for refractory epilepsy related to MCDs, it is important to achieve a better understanding of the underlying mechanisms of epileptogenesis, but this is complicated by the wide variety of different radiographic, histopathological, and molecular features of these disorders. A subset of MCDs share a number of characteristic cellular and molecular abnormalities due to early defects in neuronal and glial proliferation and differentiation and have a particularly high incidence of epilepsy, suggesting that this category of MCDs with abnormal glioneuronal proliferation may also share a common set of primary mechanisms of epileptogenesis. This review critically analyzes both clinical and basic science evidence for overlapping mechanisms of epileptogenesis in this group of disorders, focusing on tuberous sclerosis complex, focal cortical dysplasia with balloon cells, and gangliogliomas. Specifically, the role of lesional versus perilesional regions, circuit versus cellular/molecular defects, and nonneuronal factors, such as astrocytes, in contributing to epileptogenesis in these MCDs is examined. An improved understanding of these various factors involved in epileptogenesis has direct clinical implications for optimizing current treatments or developing novel therapeutic approaches for epilepsy in these disorders. [source] Consistent Localization of Interictal Epileptiform Activity on EEGs of Patients with Tuberous Sclerosis ComplexEPILEPSIA, Issue 3 2005Floor E. Jansen Summary:,Purpose: We addressed consistent localization of focal interictal epileptiform activity on EEGs of patients with tuberous sclerosis complex (TSC) and epilepsy. Methods: Twenty-one patients with TSC with a 10-year history of epilepsy and interictal epileptiform activity in three or more EEG recordings were included. None of the patients had undergone epilepsy surgery. Local maxima of interictal epileptiform activity were measured from 76 EEG traces and 33 EEG reports. Information about the patients' clinical course was extracted from their medical records. Magnetic resonance imaging (MRI) and neuropsychological examinations were performed. Statistical analysis was performed with the Mann,Whitney U test. Results: In eight patients, interictal epileptiform activity was consistently detected in one or two regions (group 1), and in 13 patients, epileptiform activity was detected in three or more regions (group 2). The number of foci increased throughout the disease course in both groups. Age at seizure onset and IQ were significantly higher in group 1. Complex partial seizures occurred more often in the patients of group 1. In 19 of the 21 patients, the most consistent epileptiform activity was localized in the frontotemporal region. Conclusions: Ninety percent of patients with TSC showed at least one region of consistent interictal epileptiform activity. Patients with one or two regions of epileptiform activity were older at seizure onset, often experienced complex partial seizures, and had mild or no mental deficits. These patients may be candidates for epilepsy surgery. [source] Lamotrigine Therapy of Epilepsy in Tuberous SclerosisEPILEPSIA, Issue 7 2001David Neal Franz Summary: ,Purpose: Lamotrigine (LTG), a newer antiepileptic drug (AED), has activity against both partial-onset and generalized seizures. Its reported benefits for behavior, and its effectiveness in Lennox,Gastaut syndrome and other forms of refractory epilepsy, make it a logical choice for treatment of epilepsy in tuberous sclerosis complex (TSC). We present our experience with LTG therapy of epilepsy in 57 patients with TSC. Methods: Patients fulfilled the diagnostic criteria for clinically definite TSC. LTG was initiated and increased until improvement in seizure frequency was noted, intolerable side effects occurred, or maximal doses were reached. Seizure frequency and behavioral changes were recorded during LTG therapy and compared with those prior to the introduction of LTG. Results: Twenty-four (42%) were seizure free, and 21 (37%) had a >50% reduction in seizure frequency. Eighteen (32%) had subjectively improved behavior and/or alertness with daily activities. Thirty-eight (67%) had no change in this regard, whereas one (2%) became worse. Responders were more likely to not have a history of infantile spasms, and to have experienced only partial seizures (p < 0.05). Otherwise no phenotypic correlations with response were apparent. Conclusions: Among patients with TSC and epilepsy, LTG was effective and well tolerated, including as initial monotherapy. Improved alertness and behavior were apparent in many patients. The incidence of side effects is similar to that reported for other pediatric populations with symptomatic partial epilepsy. The usefulness of LTG in TSC may relate to an underlying defect of glutamatergic neurotransmission in partial epilepsy. [source] All in the family: Using inherited cancer syndromes to understand de-regulated cell signaling in brain tumorsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2007S. Sean Houshmandi Abstract The cell signaling pathways that are tightly regulated during development are often co-opted by cancer cells to allow them to escape from the constraints that normally limit cell growth and cell movement. In this regard, de-regulated signaling in cancer cells confers a number of key tumor-associated properties, including increased cell proliferation, decreased cell death, and increased cell motility. The identification of some of these critical signaling pathways in the nervous system has come from studies of inherited cancer syndromes in which affected individuals develop brain tumors. The study of brain tumors arising in patients with neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and tuberous sclerosis complex (TSC) has already uncovered several key intracellular signaling pathways important for modulating brain tumor growth. An in-depth analysis of these intracellular signaling pathways will not only lead to an improved understanding of the process of brain tumorigenesis, but may also provide important molecular targets for future therapeutic drug design. J. Cell. Biochem. 102: 811,819, 2007. © 2007 Wiley-Liss, Inc. [source] What can we learn from tuberous sclerosis complex (TSC) about autism?JOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 10 2008P. J. De Vries Tuberous Sclerosis Complex (TSC) is now recognized as one of the medical conditions most commonly associated with autism. Between 1,5% of those with autism have TSC and up to 50% of people with TSC meet criteria for an autism spectrum disorder. The clinical characteristics of autism in TSC are qualitatively indistinguishable from those of idiopathic autism. So, what can TSC teach us about autism? We will present an overview of the neuropsychiatric features of TSC and will proceed with an examination of aetiological models of autism in TSC. Structural models (suggesting that autism is caused by brain lesions in specific neuroanatomical locations) and seizure models (suggesting that the age, type and control of seizures may predict autism) have both received some support, but with limited replication. More recently, molecular approaches have suggested that dysregulation of intracellular signalling through the TSC1/2-mTOR pathway may be sufficient to lead to socialization deficits and autism, and that drugs that act as mTOR inhibitors may reverse some aspects of the learning and social deficits in TSC. [source] A patient with TSC1 germline mutation whose clinical phenotype was limited to lymphangioleiomyomatosisJOURNAL OF INTERNAL MEDICINE, Issue 2 2004T. Sato Abstract. Background:, Lymphangioleiomyomatosis (LAM) can occur as in isolated form (sporadic LAM) or as a pulmonary manifestation of tuberous sclerosis complex (TSC) (TSC-associated LAM). Recent studies, however, revealed that both forms of LAM are genetically related but that sporadic LAM is a distinct clinical entity caused by somatic mutations of TSC2 (not TSC1) rather than a forme fruste of TSC carrying either of the TSC1 or TSC2 germline mutations. Method:, Case presentation and in-depth molecular and histopathological examinations. A 34-year-old Japanese woman was diagnosed as having pulmonary lymphangioleiomyomatosis (LAM) when bilateral pneumothoraces were surgically treated in 1992. Although slowly progressive renal disfunction was observed due to bilateral multiple renal cysts during the past 4 years, she had no other clinical features of TSC and was diagnosed as having sporadic LAM with multiple renal cysts of undetermined aetiology. Her subsequent clinical course was complicated by an endobrochial carcinoid tumour, which eventually resulted in her death in June 1999 due to massive haemoptysis. Results:, Postmortem examination revealed the presence of LAM lesions in the lungs, mediastinal lymph nodes, kidneys and uterus. Diffuse renal LAM lesions are presumed to generate multiple renal cysts by constricting the nephron rather than epithelial hyperplasia obstructing lumina, which is analysis of the TSC genes demonstrated that she did not have TSC2/PKD1 contiguous gene syndrome but had a TSC1 germline mutation (Sato T et al. J Hum Genet 2002; 47: 20,8) that had occured de novo. Conclusion:, This patient therefore illustrates that clinical manifestations of TSC are sufficiently diverse as to allow a forme fruste of TSC that mimics sporadic LAM and that TSC1 mutation can cause multiple renal cysts resulting in renal failure. [source] Molecular activity of sirolimus and its possible application in tuberous sclerosis treatmentMEDICINAL RESEARCH REVIEWS, Issue 2 2006Jaroslaw Jozwiak Abstract Sirolimus is one of the intensively investigated drugs with pluripotent activities. It binds to its intracellular receptor FKBP12 (FK506-binding protein 12), a member of the family of FK506-binding proteins, and inhibits the activity of mTOR, a serine/threonine kinase involved in numerous cell processes linked to cell growth control. The drug is currently registered for the prophylaxis of organ rejection and for use in coronary stents. However, unique characteristics of sirolimus make it a good candidate for anti-cancer therapy. Indeed, phase II and III clinical studies in humans with several types of neoplasms are already under way. The review describes molecular activity of sirolimus and its analogs, characteristic for specific applications, in view of very recent advances involving tuberous sclerosis complex (TSC)-mediated signaling pathways. Current studies with sirolimus performed in tuberous sclerosis animal models are presented. Possible application of sirolimus for treating tuberous sclerosis, disease caused by mutations of TSC proteins, is discussed. © 2005 Wiley Periodicals, Inc. Med Res Rev [source] Solitary subependymal giant cell astrocytoma incidentally found at autopsy in an elderly woman without tuberous sclerosis complexNEUROPATHOLOGY, Issue 2 2009Hidehiro Takei Subependymal giant cell astrocytoma (SEGA) is a benign, slowly growing tumor typically occurring in the setting of tuberous sclerosis complex (TSC). However there are several reported cases in which patients with a solitary SEGA had no other stigmata of TSC. We describe a case of SEGA in a 75-year-old woman representing the oldest patient reported to-date. The patient had a history of radical vulvectomy for malignant melanoma (MM), and died of autopsy-confirmed widespread systemic metastasis. Postmortem examination of the brain revealed a single 2.1 × 1.0 × 0.8 cm intraventricular nodule in the lateral ventricle. Histologically, it was composed of interlacing bundles of spindle-shaped tumor cells with thin delicate processes admixed with relatively large pleomorphic cells with abundant glassy eosinophilic cytoplasm, as seen in a SEGA. Immunohistochemically, GFAP, S-100 protein, and neuron specific enolase were positive, and synaptophysin labeled a few tumor cells. Also noted were rare isolated MM cells within the tumor (i.e., tumor-to-tumor metastasis). Autopsy showed no manifestations of TSC systemically or intracranially. The histopathological differential diagnosis was limited and included giant cell ependymoma and, much less likely, giant cell glioblastoma and pleomorphic xanthoastrocytoma. This case illustrates that SEGA can be found incidentally in an elderly individual with no associated symptoms and also indicates that SEGA can occur outside the setting of TSC. Tumor metastasis to an occult SEGA is extremely rare. [source] Clinicopathological and immunohistochemical findings in an autopsy case of tuberous sclerosis complexNEUROPATHOLOGY, Issue 6 2008Karin Boer Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder caused by mutations in either the TSC1 or TSC2 genes and characterized by developmental brain abnormalities. In the present study we discuss the neuropathological findings of a 32-year-old patient with a germ-line mutation in the TSC2 gene. Post mortem MRI combined with histology and immunocytochemical analysis was applied to demonstrate widespread anatomical abnormalities of gray and white matter structure. TSC brain lesions were analyzed for loss of heterozygosity (LOH) on chromosome 16p13. The neuropathological supratentorial abnormalities were represented by multiple subependymal nodules (SENs) and cortical tubers. In addition to cerebral cortical lesions, cerebellar lesions and hippocampal sclerosis were also observed. LOH was not found in the cortical tubers and SENs of this patient. Immunocytochemical analysis of the TSC brain lesions confirmed the cell-specific activation of the mTOR pathway in cortical tubers, SENs and cerebellum, as well as differential cellular localization of hamartin and tuberin, the TSC1 and TSC2 gene products. Examination of the pathological brain regions revealed activated microglial cells and disruption of blood-brain barrier permeability. Predominant intralesional cell-specific distribution was also detected for the multidrug transporter protein P-gp, possibly explaining the mechanisms underlying the pharmacoresistance to antiepileptic drugs. Autopsy findings confirm the complexity of the brain abnormalities encountered in TSC patients and proved useful in clarifying certain aspects of the pathogenesis, epileptogenesis and pharmacoresistance of TSC lesions. [source] Mutational and expression analysis of CDK1, cyclinA2 and cyclinB1 in epilepsy-associated glioneuronal lesionsNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 2 2007V. Schick Gangliogliomas and focal cortical dysplasias (FCDs) constitute glioneuronal lesions, which are frequently encountered in biopsy specimens of patients with pharmacoresistant focal epilepsy and relate to impaired differentiation and migration of neural precursors. However, their molecular pathogenesis and relationship are still largely enigmatic. Recent data suggest several components of the insulin-pathway, including TSC1 and TSC2 mutated in tuberous sclerosis complex (TSC), to be altered in gangliogliomas and FCD with Taylor type balloon cells (FCDIIb). The proteins tuberin (TSC2) and hamartin (TSC1) constitute a tumour suppressor mechanism involved in cell-cycle control. Hamartin and/or tuberin were reported to colocalize and/or interact with CDK1, cyclinB1 and cyclinA2 that are critically involved in cell-size and cell-growth control. Here, we have carried out mutational and expression analyses of CDK1, cyclinB1 and cyclinA2 in gangliogliomas and FCDIIb. Mutational screening was performed by single-strand conformation polymorphism analysis in gangliogliomas (n = 20), FCDIIb (n = 35) and controls. CyclinB1 revealed a polymorphism (G to A, cDNA Position 966, GenBank: NM_031966) in exon 7 with similar frequencies in FCDIIb, gangliogliomas and control specimens (FCD n = 9/35; gangliogliomas n = 5/20; control n = 20/100). We used real-time reverse transcription polymerase chain reaction to determine expression levels of CDK1, cyclinB1 and cyclinA2 in 10 FCDIIb and nine gangliogliomas compared with unaffected adjacent control tissue of the same patients. We observed significantly lower expression of CDK1 and cyclinA2 in FCDIIb vs. controls whereas no significant expression differences were present for CDK1, cyclinB1 and cyclinA2 in gangliogliomas. Our data strongly argue against mutational events of CDK1, cyclinB1 and cyclinA2 to play a role in gangliogliomas or FCDIIb. However, a potential functional significance of lower expression for the cell-size and cell-cycle regulators CDK1 and cyclinA2 in FCDIIb composed of large dysplastic neurones and balloon cells needs to be further resolved. [source] Sirolimus therapy for fibromatosis and multifocal renal cell carcinoma in a child with tuberous sclerosis complex,PEDIATRIC BLOOD & CANCER, Issue 7 2010Joseph G. Pressey MD Abstract A male with tuberous sclerosis complex (TSC) developed a chest wall fibromatosis and bilateral multifocal renal cell carcinoma (RCC). The fibromatosis tumor was initially resected during infancy but recurred 5 years later. At that time, bilateral RCC was also detected, leading to the resection of the more extensively affected right kidney. In an attempt to avoid bilateral nephrectomies, the patient was treated with the mTOR inhibitor sirolimus. Within 6 months of therapy, the fibromatosis and remaining RCC tumors responded substantially with minimal adverse effects. Pediatr Blood Cancer 2010;54:1035,1037 © 2010 Wiley-Liss, Inc. [source] Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complexANNALS OF NEUROLOGY, Issue 4 2008Ling-Hui Zeng MD Objective Tuberous sclerosis complex (TSC) represents one of the most common genetic causes of epilepsy. TSC gene inactivation leads to hyperactivation of the mammalian target of rapamycin signaling pathway, raising the intriguing possibility that mammalian target of rapamycin inhibitors might be effective in preventing or treating epilepsy in patients with TSC. Mice with conditional inactivation of the Tsc1 gene primarily in glia (Tsc1GFAPCKO mice) develop glial proliferation, progressive epilepsy, and premature death. Here, we tested whether rapamycin could prevent or reverse epilepsy, as well as other cellular and molecular brain abnormalities in Tsc1GFAPCKO mice. Methods Tsc1GFAPCKO mice and littermate control animals were treated with rapamycin or vehicle starting at postnatal day 14 (early treatment) or 6 weeks of age (late treatment), corresponding to times before and after onset of neurological abnormalities in Tsc1GFAPCKO mice. Mice were monitored for seizures by serial video-electroencephalogram and for long-term survival. Brains were examined histologically for astrogliosis and neuronal organization. Expression of phospho-S6 and other molecular markers correlating with epileptogenesis was measured by Western blotting. Results Early treatment with rapamycin prevented the development of epilepsy and premature death observed in vehicle-treated Tsc1GFAPCKO mice. Late treatment with rapamycin suppressed seizures and prolonged survival in Tsc1GFAPCKO mice that had already developed epilepsy. Correspondingly, rapamycin inhibited the abnormal activation of the mammalian target of rapamycin pathway, astrogliosis, and neuronal disorganization, and increased brain size in Tsc1GFAPCKO mice. Interpretation Rapamycin has strong efficacy for preventing seizures and prolonging survival in Tsc1GFAPCKO mice. Ann Neurol 2008 [source] Angiomyolipomata: challenges, solutions, and future prospects based on over 100 cases treatedBJU INTERNATIONAL, Issue 1 2010Prasanna Sooriakumaran Study Type , Therapy (case series) Level of Evidence 4 OBJECTIVE To examine the presentation, management and outcomes of patients with renal angiomyolipoma (AML) over a period of 10 years, at St George's Hospital, London, UK. PATIENTS AND METHODS We assessed retrospectively 102 patients (median follow-up 4 years) at our centre; 70 had tuberous sclerosis complex (TSC; median tumour size 3.5 cm) and the other 32 were sporadic (median tumour size 1.2 cm). Data were gathered from several sources, including radiology and clinical genetics databases. The 77 patients with stable disease were followed up with surveillance imaging, and 25 received interventions, some more than one. Indications for intervention included spontaneous life-threatening haemorrhage, large AML (10,20 cm), pain and visceral compressive symptoms. RESULTS Selective arterial embolization (SAE) was performed in 19 patients; 10 received operative management and four had a radiofrequency ablation (RFA). SAE was effective in controlling haemorrhage from AMLs in the acute setting (six) but some patients required further intervention (four) and there was a significant complication rate. The reduction in tumour volume was only modest (28%). No complications occurred after surgery (median follow-up 5.5 years) or RFA (median follow-up 9 months). One patient was entered into a trial and treated with sirolimus (rapamycin). CONCLUSIONS The management of AML is both complex and challenging, especially in those with TSC, where tumours are usually larger and multiple. Although SAE was effective at controlling haemorrhage in the acute setting it was deemed to be of limited value in the longer term management of these tumours. Thus novel techniques such as focused ablation and pharmacological therapies including the use of anti-angiogenic molecules and mTOR inhibitors, which might prove to be safer and equally effective, should be further explored. [source] Upper pole access for complex lower pole renal calculiBJU INTERNATIONAL, Issue 6 2004Monish Aron Authors from New Delhi assessed the efficacy of superior pole access for complex lower pole calyceal calculi; they found this to be the best way of approaching such complex stones, allowing faster and better clearance with a single puncture. The second paper in this section is from authors from the UK who set out to describe the frequency of renal symptoms and complications in patients with tuberous sclerosis complex, and to relate the history of renal haemorrhage with renal lesions identified on renal scan. OBJECTIVES To assess the efficacy of superior pole access for complex lower pole calyceal calculi. PATIENTS AND METHODS In all, 102 patients with complex inferior calyceal calculi were included in a prospective unrandomized study. Complex inferior calyceal calculi were defined as multiple calculi in two or more inferior calyces of the lower polar group, with each calyx draining through a separate infundibulum and at an acute angle to each other. In 33 patients (32%; group 1) an inferior calyceal puncture was made and in 69 (68%; group 2) access was obtained through a superior calyceal puncture. The stone-free rates, decrease in haemoglobin, operative duration, requirement for additional tracts and second procedures in the two groups were compared. RESULTS Stone clearance rates and blood loss values were better in group 2, although they were not significantly different. The mean operative duration, number of tracts required and the re-look procedure rate was significantly less in group 2. Two patients (3%) in group 2 had hydrothorax related to supracostal puncture and required chest tube insertion. CONCLUSIONS Superior calyceal puncture (supracostal or infracostal) affords optimum access to complex inferior calyceal stones, providing faster and better clearance with a single puncture, and less requirement for second-look procedures. [source] An epidemiological study of renal pathology in tuberous sclerosis complexBJU INTERNATIONAL, Issue 6 2004Finbar J. O'Callaghan OBJECTIVES To report the frequency of renal symptoms and complications of patients with tuberous sclerosis complex (TSC), to describe the ultrasonographic appearance of the kidneys in a population-based sample, and to investigate the relationship between a history of renal haemorrhage and renal lesions identified by ultrasonography. PATIENTS AND METHODS As part of an epidemiological study, 179 patients with TSC were identified as living in the Wessex Region in the South of England. Patients were interviewed and examined in their homes, to elicit the presence of renal symptoms or a history of renal complications. Renal ultrasonography was used in consenting patients in their homes. RESULTS There was a history of renal complications in 16 (9%) patients; 149 consented to interview and examination, and 19 gave a history of renal symptoms in the previous year; 124 had renal ultrasonography; 86 (69%) had renal angiomyolipomas and 37 (30%) had renal cysts. Large lesions (>3 cm in diameter) were strongly associated with a history of symptomatic bleeding, although significant haemorrhage occurred in a 6-year-old child with small angiomyolipomas. CONCLUSIONS The formation of angiomyolipoma in TSC is common. Polycystic kidney disease, renal carcinoma and renal failure, although rare, occur in TSC. Most patients with angiomyolipomas have neither complications nor symptoms. There was no appreciable difference between the sexes in the risk of developing these lesions. Although less commonly seen in the very young, there is no identifiable relationship after adolescence between age and the risk of having a renal angiomyolipoma. Bleeding tends to occur from large lesions (>3 cm) but most such patients have remained asymptomatic to date. [source] | ||||||||||||||||||||||||||||