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)

To assess cognitive outcome in patients with tuberous sclerosis complex (TSC) and identify predictive risk factors, we reviewed records of 107 patients who underwent comprehensive neuropsychiatric evaluation. Fifty-seven percent of patients with TSC had normal-range IQ/developmental quotient (DQ). Cognitive outcome was strongly associated with refractory seizures and TSC2 mutation. In TSC, IQ/DQ is bimodally distributed, and more than half of individuals are in the normal range.
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PMID:Cognitive prognosis of patients with tuberous sclerosis complex. 1720 Apr 95

Tuberous sclerosis complex (TSC) is a congenital syndrome characterized by the widespread development of benign tumors in multiple organs, caused by mutations in one of the tumor suppressor genes, TSC1 or TSC2. About 80% of affected patients have a new mutation, and the remaining 20% have inherited a TSC gene mutation from a parent. The disorder affects approximately 1 in 6000 individuals. Cortical tubers are the neuropathological hallmark of TSC. The most common neurological manifestations of TSC are epilepsy, mental retardation, and autistic behavior. Epilepsy occurs in up to 80-90% of patients and is often intractable, with a poor response to anticonvulsant medications. While the molecular basis of TSC is well established, far less is known about the mechanisms of epilepsy in this disorder. In this article, we first summarize known clinical aspects of TSC with emphasis on its neurological features. Then, based on the molecular, pathological, immunohistochemical, neurochemical, and physiological properties of tubers in patients with TSC and in animal models, we discuss possible mechanisms of seizures and epileptogenesis in TSC. Finally, we provide an updated literature review and a consensus statement from the Tuberous Sclerosis Complex Working Group for future research into the mechanisms of epilepsy in TSC.
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PMID:Tuberous sclerosis complex and epilepsy: recent developments and future challenges. 1769 54

Tuberous sclerosis (TSC) is a hamartoma syndrome caused by mutations in TSC1 or TSC2 in which cerebral cortical tubers and seizures are major clinical issues. We have engineered mice in which most cortical neurons lose Tsc1 expression during embryonic development. These Tsc1 mutant mice display several neurological abnormalities beginning at postnatal day 5 with subsequent failure to thrive and median survival of 35 d. The mice also display clinical and electrographic seizures both spontaneously and with physical stimulation, and some seizures end in a fatal tonic phase. Many cortical and hippocampal neurons are enlarged and/or dysplastic in the Tsc1 mutant mice, strongly express phospho-S6, and are ectopic in multiple sites in the cortex and hippocampus. There is a striking delay in myelination in the mutant mice, which appears to be caused by an inductive neuronal defect. This new TSC brain model replicates several features of human TSC brain lesions and implicates an important function of Tsc1/Tsc2 in neuronal development.
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PMID:A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. 1752

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

Low-grade glioneuronal lesions involving tumors such as gangliogliomas and focal cortical dysplasias (FCD) predispose individuals to pharmacoresistant epilepsy. A frequent variant of FCD is composed of dysplastic cytomegalic neurons and Taylor-type balloon cells (FCD(IIb)). Those are similar to cellular elements, which are present in cortical tubers in the autosomal dominant inherited tuberous sclerosis complex (TSC). This phacomatosis is caused by mutations in the TSC1 or TSC2 genes. Recent data have indicated accumulation of distinct allelic variants of TSC1 also in FCD(IIb). TSC1 represents a key factor in the phosphatidylinositol 3-kinase (PI3K) pathway. A variety of alterations in the PI3K-pathway have been recently reported in epilepsy-associated glioneuronal malformations. Here, we discuss pathogenetic similarities and differences between cortical dysplasias as well epilepsy-associated glioneuronal tumors and TSC-associated cortical tubers with a focus on PI3K-pathway components including ezrin, radixin and moesin (ERM), which represent downstream effectors involved in cytoskeleton-membrane interference. No evidence has been found for mutational events of ERM genes to play a major pathogenetic role in epilepsy-associated glioneuronal malformations. In contrast, aberrant expression of ERM proteins in FCDs and gangliogliomas was observed. These alterations may relate to compromised interactions of dysplastic cellular components in epilepsy-associated glioneuronal lesions and be involved in aberrant PI3K-pathway signaling in epilepsy-associated malformations. However, the underlying cause of PI3K-pathway activation and the functional relationship of PI3K-pathway activity to generation of seizures in epilepsy-associated glioneuronal lesions will need to be determined in the future.
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PMID:Alterations of phosphatidylinositol 3-kinase pathway components in epilepsy-associated glioneuronal lesions. 1791 May 83

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 is a single-gene disorder caused by heterozygous mutations in the TSC1 (9q34) or TSC2 (16p13.3) gene and is frequently associated with mental retardation, autism and epilepsy. Even individuals with tuberous sclerosis and a normal intelligence quotient (approximately 50%) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits. Here we report that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2(+/-) mice) show deficits in learning and memory. Cognitive deficits in Tsc2(+/-) mice emerged in the absence of neuropathology and seizures, demonstrating that other disease mechanisms are involved. We show that hyperactive hippocampal mammalian target of rapamycin (mTOR) signaling led to abnormal long-term potentiation in the CA1 region of the hippocampus and consequently to deficits in hippocampal-dependent learning. These deficits included impairments in two spatial learning tasks and in contextual discrimination. Notably, we show that a brief treatment with the mTOR inhibitor rapamycin in adult mice rescues not only the synaptic plasticity, but also the behavioral deficits in this animal model of tuberous sclerosis. The results presented here reveal a biological basis for some of the cognitive deficits associated with tuberous sclerosis, and they show that treatment with mTOR antagonists ameliorates cognitive dysfunction in a mouse model of this disorder.
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PMID:Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. 1856 33

Self-injurious behavior (SIB) has been observed in people with tuberous sclerosis complex (TSC), although the frequency of SIB in TSC is largely unknown. SIB is associated with intellectual and developmental disabilities, but there is no single cause of SIB. We retrospectively examined the frequency of SIB in a population of 257 patients with TSC and determined possible associations with SIB. We found a 10% frequency of SIB in our TSC population. When compared with patients without psychiatric symptoms, we identified a significantly higher rate of electroencephalographic interictal spikes in the left frontal lobe and a significantly lower number of tubers in the left occipital, parietal, and posterior temporal lobes. We also found that frequency of TSC2 mutation, history of infantile spasms, history of seizures, mental retardation, and autism are significantly associated with SIB.
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PMID:Self-injurious behavior and tuberous sclerosis complex: frequency and possible associations in a population of 257 patients. 1870 61

Tuberous sclerosis complex (TSC) is characterised by seizures, mental retardation and the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene or the TSC2 gene. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). We have developed a straightforward, semiautomated in-cell western (ICW) assay to investigate the effects of amino acid changes on the TSC1-TSC2-dependent inhibition of mTOR activity. Using this assay, we have characterised 20 TSC2 variants identified in individuals with TSC or suspected of having the disease. In 12 cases, we concluded that the identified variant was pathogenic. The ICW is a rapid, reproducible assay, which can be applied to the characterisation of the effects of novel TSC2 variants on the activity of the TSC1-TSC2 complex.
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PMID:A reliable cell-based assay for testing unclassified TSC2 gene variants. 1885 62

Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder with variable phenotypic expression, due to a mutation in one of the two genes, TSC1 and TSC2, and a subsequent hyperactivation of the downstream mTOR pathway, resulting in increased cell growth and proliferation. The central nervous system is consistently involved in TSC, with 90% of individuals affected showing structural abnormalities, and almost all having some degree of CNS clinical manifestations, including seizures, cognitive impairment and behavioural problems. TSC is proving to be a particularly informative model for studying contemporary issues in developmental neurosciences. Recent advances in the neurobiology of TSC from molecular biology, molecular genetics, and animal model studies provide a better understanding of the pathogenesis of TSC-related neurological symptoms. Rapamycin normalizes the dysregulated mTOR pathway, and recent clinical trials have demonstrated its efficacy in various TSC manifestations, suggesting the possibility that rapamycin may have benefit in the treatment of TSC brain disease.
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PMID:Recent advances in neurobiology of Tuberous Sclerosis Complex. 1902 34


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