Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor syndrome that affects approximately 1 in 6000 individuals. It is characterized by the development of tumors, named hamartomas, in the kidneys, heart, skin and brain. The latter often cause seizures, mental retardation, and a variety of developmental disorders, including autism. This disease is caused by mutations within the tumor suppressor gene TSC1 on chromosome 9q34 encoding hamartin or within TSC2 on chromosome 16p13.3 encoding tuberin. TSC patients carry a mutant TSC1 or TSC2 gene in each of their somatic cells, and loss of heterozygosity has been documented in a wide variety of TSC tumors. Recent data suggest that functional inactivation of TSC proteins might also be involved in the development of other diseases not associated with TSC, such as sporadic bladder cancer, breast cancer, ovarian carcinoma, gall bladder carcinoma, non-small-cell carcinoma of the lung, and Alzheimer's disease. Tuberin and hamartin form a heterodimer, suggesting they might affect the same processes. Tuberin is assumed to be the functional component of the complex and has been implicated in the regulation of different cellular functions. The TSC proteins regulate cell size control due to their involvement in the insulin signalling pathway. Furthermore, they are potent positive regulators of the cyclin-dependent kinase inhibitor p27, a major regulator of the mammalian cell cycle. Here we review the current knowledge on how mutations within the TSC genes could trigger deregulation of stability and localization of the tumor suppressor p27.
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PMID:The tuberous sclerosis genes and regulation of the cyclin-dependent kinase inhibitor p27. 1671 32

Tuberous sclerosis complex (TSC) is a multi-system disorder associated with mutations in the TSC1 (hamartin) or TSC2 (tuberin) genes. The neurocognitive features of TSC show wide variability and have generally been attributed to structural brain abnormalities and/or seizures. We review the fundamental roles of TSC1 and TSC2 in cell signalling and propose that because the hamartin-tuberin complex (hereafter referred to as TSC1-2) acts as a global regulator and integrator of a range of physiological processes ('GRIPP') the neurocognitive manifestations of TSC result directly from cell-signalling abnormalities. Under the GRIPP hypothesis, the spectrum of neurodevelopmental abnormalities is caused by the biochemical consequences of individual TSC1 and TSC2 mutations. Recognizing the importance of signalling disruption in the brain might improve our understanding of other neurocognitive disorders.
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PMID:The tuberous sclerosis complex proteins--a GRIPP on cognition and neurodevelopment. 1763 34

Tuberous sclerosis complex (TSC) is an inherited disorder resulting from mutations in one of two genes, TSC1 (Hamartin) and TSC2 (Tuberin). These two proteins form a cytosolic complex that inhibits the mTOR pathway that controls cell growth and proliferation. Pathologically, abnormalities of neuronal migration, cellular differentiation and excessive cellular proliferation all contribute to the formation of the different brain lesions of TSC. Seizure is the most common presenting symptom. Seizures can be present in the first year of life and up to one third of children develop infantile spasms. Seizures usually have a focal or multifocal origin, are often resistant to antiepileptic drugs and have a negative impact on the neurocognitive development. Vigabatrin has proved to be effective against infantile spasms due to TSC. New evidence suggests that it is possible to noninvasively identify using multimodality techniques, TSC children who are likely to become seizure-free following surgical treatment. Understanding the mechanisms of epileptogenesis and the possible role of the mTOR pathway in this process might increase the availability of novel and targeted therapies.
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PMID:Management of epilepsy in tuberous sclerosis complex. 1834 74

Tuberous sclerosis complex is a genetic multisystem disease characterized by hamartic development of many organs, most notably the brain, heart, kidneys, lungs, and skin. This autosomic dominant disorder results from mutations in one of two genes, TSC1 and TSC2, coding for hamartin and tuberin, respectively. The hamartin-tuberin complex inhibits the mammalian target of rapamycin pathway, which controls cell growth and proliferation. The clinical presentation is highly variable and most features of tuberous sclerosis become evident only in childhood after the child is several years of age, limiting their usefulness for early diagnosis. The aim of this article is to define the pediatric clinical manifestations of tuberous sclerosis in correlation with patient age. Sometimes, a prenatal diagnosis can be made based on fetal ultrasound and MRI, which show cardiac and brain lesions. However, newborns are most often asymptomatic. In the 1st year, seizures are the most common symptoms, with a high incidence of infantile spasms. In children between 2 and 10 years of age, neurological symptoms are the most frequent with epilepsy, mental retardation, and autism, but extraneurological manifestations can be diagnosed. In adolescents, most features of tuberous sclerosis become evident and renal and pulmonary manifestations must be sought. The knowledge of age-dependent clinical features of tuberous sclerosis can provide an earlier diagnosis and improve the management of these patients with a special role for multidisciplinary consultation.
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PMID:[Characteristics of tuberous sclerosis in children]. 2070 8

Tuberous Sclerosis Complex (TSC) is an autosomal dominant, multi-system disorder, typically involving severe neurological symptoms, such as epilepsy, cognitive deficits and autism. Two genes, TSC1 and TSC2, encoding the proteins hamartin and tuberin, respectively, have been identified as causing TSC. Although there is a substantial overlap in the clinical phenotype produced by TSC1 and TSC2 mutations, accumulating evidence indicates that TSC2 mutations cause more severe neurological manifestations than TSC1 mutations. In this study, the neurological phenotype of a novel mouse model involving conditional inactivation of the Tsc2 gene in glial-fibrillary acidic protein (GFAP)-positive cells (Tsc2(GFAP1)CKO mice) was characterized and compared with previously generated Tsc1(GFAP1)CKO mice. Similar to Tsc1(GFAP1)CKO mice, Tsc2(GFAP1)CKO mice exhibited epilepsy, premature death, progressive megencephaly, diffuse glial proliferation, dispersion of hippocampal pyramidal cells and decreased astrocyte glutamate transporter expression. However, Tsc2(GFAP1)CKO mice had an earlier onset and higher frequency of seizures, as well as significantly more severe histological abnormalities, compared with Tsc1(GFAP1)CKO mice. The differences between Tsc1(GFAP1)CKO and Tsc2(GFAP1)CKO mice were correlated with higher levels of mammalian target of rapamycin (mTOR) activation in Tsc2(GFAP1)CKO mice and were reversed by the mTOR inhibitor, rapamycin. These findings provide novel evidence in mouse models that Tsc2 mutations intrinsically cause a more severe neurological phenotype than Tsc1 mutations and suggest that the difference in phenotype may be related to the degree to which Tsc1 and Tsc2 inactivation causes abnormal mTOR activation.
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PMID:Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex. 2106 1

Tuberous sclerosis (TS) is an autosomal dominant disorder characterized by benign hamartomas in multiple organ systems, including rhabdomyomas in the heart and subependymal giant cell astrocytomas in the brain. Mutations in the hamartin (TSC1) and tuberin (TSC2) genes have been identified as causative. We report an infant who presented with seizures and cardiac rhabdomyomas and whose diagnosis of TS was confirmed by a TSC2 C1605T nonsense mutation. In addition, we review the literature of cardiac tumors. Despite the typical natural history of tumor regression, lifelong follow-up is necessary for the appropriate management of these patients. Elucidation of the genetics and pathogenesis of cardiac tumors, as illustrated by the TS rhabdomyoma described in this case, may lead to novel therapies.
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PMID:Tuberous sclerosis and cardiac rhabdomyomas: a case report and review of the literature. 2141 39

We report the first case of gastric cancer in association with tuberous sclerosis. Tuberous sclerosis is an autosomal dominant disorder which presents with a constellation of signs including benign tumours in the brain and in other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, developmental delay, behavioural problems, skin abnormalities, and lung and kidney disease. It is caused by mutations on either of two genes, tuberous sclerosis genes, TSC1 or TSC2, which encode for the proteins hamartin and tuberin respectively. These proteins act as tumour growth suppressor agents that regulate cell proliferation and differentiation. Tuberous sclerosis has been associated with hamartomatous growths and angiomyolipomas, an association with gastric cancer has not been reported; however, this could be a co-incidental finding and further cases need to be reported.
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PMID:Gastric Adenocarcinoma in Association with Tuberous Sclerosis: Case report. 2150 79

Tuberous Sclerosis Complex (TSC) is an inherited disorder resulting from mutations in one of two tumor suppressor genes: TSC1 (hamartin) and TSC2 (tuberin). Hamartin and tuberin, the protein products of TSC1 and TSC2, form a functional protein complex in the mTOR pathway that controls cell growth and proliferation. Epilepsy is the most common disorder in TSC, frequently associated with intractable and early onset seizures, and often as infantile spasms. Epilepsy surgery is an option for TSC patients with medically intractable epilepsy. Multimodality neuroimaging has improved the detection of epileptogenic foci, allowing an increased number of TSC patients to be evaluated noninvasively for resective surgery. Advances in understanding of the molecular pathogenesis of the TSC are crucial to establish new therapeutic approaches for individuals with TSC.
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PMID:Tuberous sclerosis and epilepsy. 2151 26

Challenges facing children with epilepsy are understanding the neurobiology of pharmacoresistance of epileptic encephalopathies and the development of effective surgical treatment options for those with "non-lesional" epilepsy. Although, understanding the genetics of childhood epilepsy has advanced, an effective treatment intervention has not occurred. Recently, understanding the neurobiology of hamartin and tuberin in the development of epilepsy and cognitive impairment associated with tuberous sclerosis complex allowed the development of sirolimus and everolimus to be used in human clinical trials. In spite of these breakthroughs a large number of children are likely to be outside the scope of interventional therapies. For such patients the burden of seizures is onerous and psycho-social consequences debilitating. Surgical resective options are often limited by the lack of a well defined epileptic lesion. Co-registered synthesis of advanced functional, structural and electrographic seizure onset allows identification of a focus in patients thought to have "non-lesional" epilepsy. Developments of a Pipeline for prospective data sharing are likely to increase understanding and validation of the epileptogenic zone and offer the hope of seizure freedom. Two outstanding young investigators provide a review of their exciting research and its implications in pediatric epilepsy.
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PMID:Pediatric epileptology. 2153 Apr 13

Tuberous sclerosis complex is a genetic disorder characterized by the formation of nonmalignant hamartomas in the brain, heart, skin, kidney, lung, and other organs. It is associated with autism, epilepsy, and other neurocognitive and behavioral disabilities. Wide phenotypic variation occurs in disease severity and natural course: some patients demonstrate minimal effects, e.g., skin changes; others manifest profound seizures and mental retardation. Tuberous sclerosis complex is caused by mutations in either the tuberous sclerosis complex 1 or 2 gene (coding for hamartin and tuberin, respectively). The tuberous sclerosis complex 1/tuberous sclerosis complex 2 protein dimer complex is a crucial inhibitory element in the mammalian target of rapamycin pathway, regulating cell growth and proliferation. Until recently, few options existed, other than surgery, for treating symptoms of tuberous sclerosis complex related to the growth of hamartomas. Increased understanding of the genetic cause of the disease and underlying dysregulation of the mammalian target of rapamycin pathway has led to clinical trials of mammalian target of rapamycin inhibitors, including sirolimus and everolimus. This review gives an overview of tuberous sclerosis complex and its molecular causes, and summarizes results from recent clinical trials of mammalian target of rapamycin inhibitors in patients with the disease.
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PMID:Emerging treatments in the management of tuberous sclerosis complex. 2252 Mar 46


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