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)

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

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that is among the most common genetic causes of epilepsy. Focal brain lesions in TSC, known as cortical tubers, have been implicated in promoting epileptogenesis in TSC. Histological, cellular, and molecular abnormalities in astrocytes are characteristic features of tubers and perituberal cortex, suggesting that astrocyte dysfunction may contribute to the pathophysiology of epilepsy in TSC. Numerous astrocytes can be seen histologically in tubers expressing glial fibrillary acidic and S100 proteins. In some analyses, astrocytes exhibit enhanced activation of the mammalian target of rapamycin suggesting a link between TSC1 and TSC2 mutations and astrocytic proliferation. Astrocytic proliferation in subependymal giant cell astrocytoma is associated with progressive growth and compression of surrounding brain structures by these lesions. Increased numbers of enlarged astrocytes has been observed in several TSC mouse models and may be intimately linked to epileptogenesis. Impairment of astrocytic buffering mechanisms for glutamate and potassium has been identified in TSC animal models and human tuber tissue and likely promotes neuronal excitability and seizures in TSC. Targeting these defects in astrocytes may represent a novel therapeutic strategy for epilepsy in patients with TSC.
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PMID:Tuberous sclerosis and epilepsy: role of astrocytes. 2243 24

The mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth, differentiation, proliferation, and metabolism. Loss-of-function mutations in upstream regulators of mTOR have been highly associated with dysplasias, epilepsy, and neurodevelopmental disorders. These include tuberous sclerosis, which is due to mutations in TSC1 or TSC2 genes; mutations in phosphatase and tensin homolog (PTEN) as in Cowden syndrome, polyhydramnios, megalencephaly, symptomatic epilepsy syndrome (PMSE) due to mutations in the STE20-related kinase adaptor alpha (STRADalpha); and neurofibromatosis type 1 attributed to neurofibromin 1 mutations. Inhibition of the mTOR pathway with rapamycin may prevent epilepsy and improve the underlying pathology in mouse models with disrupted mTOR signaling, due to PTEN or TSC mutations. However the timing and duration of its administration appear critical in defining the seizure and pathology-related outcomes. Rapamycin application in human cortical slices from patients with cortical dysplasias reduces the 4-aminopyridine-induced oscillations. In the multiple-hit model of infantile spasms, pulse high-dose rapamycin administration can reduce the cortical overactivation of the mTOR pathway, suppresses spasms, and has disease-modifying effects by partially improving cognitive deficits. In post-status epilepticus models of temporal lobe epilepsy, rapamycin may ameliorate the development of epilepsy-related pathology and reduce the expression of spontaneous seizures, but its effects depend on the timing and duration of administration, and possibly the model used. The observed recurrence of seizures and epilepsy-related pathology after rapamycin discontinuation suggests the need for continuous administration to maintain the benefit. However, the use of pulse administration protocols may be useful in certain age-specific epilepsy syndromes, like infantile spasms, whereas repetitive-pulse rapamycin protocols may suffice to sustain a long-term benefit in genetic disorders of the mTOR pathway. In summary, mTOR dysregulation has been implicated in several genetic and acquired forms of epileptogenesis. The use of mTOR inhibitors can reverse some of these epileptogenic processes, although their effects depend upon the timing and dose of administration as well as the model used.
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PMID:Finding a better drug for epilepsy: the mTOR pathway as an antiepileptogenic target. 2257 18

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder with severe neurologic manifestations, including epilepsy, autism, anxiety and attention deficit hyperactivity disorder. TSC is caused by the loss of either the TSC1 or TSC2 genes that normally regulate the mammalian target of rapamycin (mTOR) kinase. mTOR exists within two distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Loss of either TSC gene leads to increased mTORC1 but decreased mTORC2 signaling. As the contribution of decreased mTORC2 signaling to neural development and homeostasis has not been well studied, we generated a conditional knockout (CKO) of Rictor, a key component of mTORC2. mTORC2 signaling is impaired in the brain, whereas mTORC1 signaling is unchanged. Rictor CKO mice have small brains and bodies, normal lifespan and are fertile. Cortical layering is normal, but neurons are smaller than those in control brains. Seizures were not observed, although excessive slow activity was seen on electroencephalography. Rictor CKO mice are hyperactive and have reduced anxiety-like behavior. Finally, there is decreased white matter and increased levels of monoamine neurotransmitters in the cerebral cortex. Loss of mTORC2 signaling in the cortex independent of mTORC1 can disrupt normal brain development and function and may contribute to some of the neurologic manifestations seen in TSC.
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PMID:Deletion of Rictor in neural progenitor cells reveals contributions of mTORC2 signaling to tuberous sclerosis complex. 2304 74

Certain mutations within the mammalian target of rapamycin (mTOR) pathway, most notably those affecting the tuberous sclerosis complex (TSC), lead to aberrant activation of mTOR and result in a high incidence of epilepsy in humans and animal models. Although hyperactivation of mTOR has been strongly linked to the development of epilepsy and, conversely, inhibition of mTOR by rapamycin treatment is protective against seizures in several models, the downstream epileptic mechanisms have remained elusive. Autophagy, a catabolic process that plays a vital role in cellular homeostasis by mediating the turnover of cytoplasmic constituents, is negatively regulated by mTOR. Here we demonstrate that autophagy is suppressed in brain tissues of forebrain-specific conditional TSC1 and phosphatase and tensin homlog knock-out mice, both of which display aberrant mTOR activation and seizures. In addition, we also discovered that autophagy is suppressed in the brains of human TSC patients. Moreover, conditional deletion of Atg7, an essential regulator of autophagy, in mouse forebrain neurons is sufficient to promote development of spontaneous seizures. Thus, our study suggests that impaired autophagy contributes to epileptogenesis, which may be of interest as a potential therapeutic target for epilepsy treatment and/or prevention.
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PMID:Impaired autophagy in neurons after disinhibition of mammalian target of rapamycin and its contribution to epileptogenesis. 2313 10

Tuberous sclerosis complex (TSC) is a genetic disease characterized by multiorgan benign tumors as well as neurological manifestations. Epilepsy and autism are two of the more prevalent neurological complications and are usually severe. TSC is caused by mutations in either the TSC1 (encodes hamartin) or the TSC2 (encodes tuberin) genes with TSC2 mutations being associated with worse outcomes. Tuberin contains a highly conserved GTPase-activating protein (GAP) domain that indirectly inhibits mammalian target of rapamycin complex 1 (mTORC1). mTORC1 dysregulation is currently thought to cause much of the pathogenesis in TSC but mTORC1-independent mechanisms may also contribute. We generated a novel conditional allele of Tsc2 by flanking exons 36 and 37 with loxP sites. Mice homozygous for this knock-in Tsc2 allele are viable and fertile with normal appearing growth and development. Exposure to Cre recombinase then creates an in-frame deletion involving critical residues of the GAP domain. Homozygous conditional mutant mice generated using Emx1(Cre) have increased cortical mTORC1 signaling, severe developmental brain anomalies, seizures, and die within 3 weeks. We found that the normal levels of the mutant Tsc2 mRNA, though GAP-deficient tuberin protein, appear unstable and rapidly degraded. This novel animal model will allow further study of tuberin function including the requirement of the GAP domain for protein stability.
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PMID:Conditional and domain-specific inactivation of the Tsc2 gene in neural progenitor cells. 2335 22

Over the past decade, there have been numerous advances in our understanding of the molecular pathogenesis of tuberous sclerosis complex (TSC). Following the identification of the TSC1 and TSC2 genes, a link to regulatory control of the mammalian target of rapamycin (mTOR) signaling pathway has paved the way for new therapeutic interventions, and now even approved therapies for TSC. Gene identification has permitted establishment of cell lines and conditional knockout mouse strains to assay how abnormalities in brain structure lead to enhanced excitability, seizures, cognitive disabilities, and other neuropsychological disorders in TSC. Furthermore, work in in vitro systems and analysis of rodent models and human tissue has allowed investigators to study how brain lesions form in TSC. Evolving questions over the next decade include understanding the high clinical variability of TSC, defining why there is a lack of clear genotype-phenotype correlations, and identifying biomarkers for prognosis and stratification. The study of TSC has in many ways reflected a paradigm "bench-to-bedside" success story that serves as a model of many other neurological disorders.
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PMID:Evolving neurobiology of tuberous sclerosis complex. 2338 24

Tuberous sclerosis complex (TSC) is an autosomal dominant monogenetic disorder that is characterized by the formation of benign tumors in several organs as well as brain malformations and neuronal defects. TSC is caused by inactivating mutations in one of two genes, TSC1 and TSC2, resulting in increased activity of the mammalian Target of Rapamycin (mTOR). Here, we explore the cytoarchitectural and functional CNS aberrations that may account for the neurological presentations of TSC, notably seizures, hydrocephalus, and cognitive and psychological impairments. In particular, recent mouse models of brain lesions are presented with an emphasis on using electroporation to allow the generation of discrete lesions resulting from loss of heterozygosity during perinatal development. Cortical lesions are thought to contribute to epileptogenesis and worsening of cognitive defects. However, it has recently been suggested that being born with a mutant allele without loss of heterozygosity and associated cortical lesions is sufficient to generate cognitive and neuropsychiatric problems. We will thus discuss the function of mTOR hyperactivity on neuronal circuit formation and the potential consequences of being born heterozygous on neuronal function and the biochemistry of synaptic plasticity, the cellular substrate of learning and memory. Ultimately, a major goal of TSC research is to identify the cellular and molecular mechanisms downstream of mTOR underlying the neurological manifestations observed in TSC patients and identify novel therapeutic targets to prevent the formation of brain lesions and restore neuronal function.
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PMID:A circuitry and biochemical basis for tuberous sclerosis symptoms: from epilepsy to neurocognitive deficits. 2348 65

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder characterized by widespread hamartomas in several organs, including the brain, heart, skin, eyes, kidney, lung, and liver. The affected genes are TSC1 and TSC2, encoding hamartin and tuberin respectively. The hamartin-tuberin complex inhibits the mammalian-target-of-Rapamycin (mTOR) pathway, which controls cell growth and proliferation. Variations in the distribution, number, size, and location of lesions cause the clinical syndrome to vary even between relatives. About 85% of children and adolescents with TSC have CNS complications, including epilepsy, cognitive impairment, challenging behavioral problems, and autism-like symptoms. Epilepsy generally begins during the first year of life, with focal seizures and spasms. The discovery of the mTOR pathway upregulation in TSC-associated lesions presents new possibilities for treatment strategy. Increasing understanding of the molecular abnormalities caused by TSC may enable improved management of the disease.
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PMID:Tuberous sclerosis. 2362 83


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