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 (TSC) is an autosomal dominant trait characterized by the widespread development of benign tumours classified as hamartoma, and is often associated with seizures and mental retardation. The patchy distribution and focal nature of the growths suggests that they might result from inactivation of a tumour suppressor gene by a two-hit process. Over the last 2 years, studies designed to investigate both germline and somatic TSC mutations have lent support to this hypothesis. Analysis of TSC-associated hamartomas has shown loss of heterozygosity for the regions of chromosomes 9 and 16 known to harbour TSC genes, consistent with the occurrence of somatic 'second-hit' mutations. Parallel investigations using pulse field gel electrophoresis have identified constitutional deletions representing 'first-hit' mutations at 16p13.3, leading to the rapid identification of one of the causative genes, TSC2. Intriguingly, the TSC2 product, tuberin, has an area of sequence homology with the GTPase activating protein rap1GAP, suggesting a possible mechanism for its role in regulating cellular growth.
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PMID:The molecular genetics of tuberous sclerosis. 784 41

Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by seizures, mental retardation, and hamartomatous lesions. Although hamartomas can occur in almost any organ, they are most common in the brain, kidney, heart, and skin. Allelic loss or loss of heterozygosity (LOH) in TSC lesions has previously been reported on chromosomes 16p13 and 9q34, the locations of the TSC2 and TSC1 genes, respectively, suggesting that the TSC genes act as tumor-suppressor genes. In our study, 87 lesions from 47 TSC patients were analyzed for LOH in the TSC1 and TSC2 chromosomal regions. Three findings resulted from this analysis. First, we confirmed that the TSC1 critical region is distal to D9S149. Second, we found LOH more frequently on chromosome 16p13 than on 9q34. Of the 28 patients with angiomyolipomas or rhabdomyomas, 16p13 LOH was detected in lesions from 12 (57%) of 21 informative patients, while 9q34 LOH was detected in lesions from only 1 patient (4%). This could indicate that TSC2 tumors are more likely than TSC1 tumors to require surgical resection or that TSC2 is more common than TSC1 in our patient population. It is also possible that small regions of 9q34 LOH were missed. Lastly, LOH was found in 56% of renal angiomyolipomas and cardiac rhabdomyormas but in only 4% of TSC brain lesions. This suggests that brain lesions can result from different pathogenic mechanisms than kidney and heart lesions.
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PMID:Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. 875 27

How the concept of the tuberous sclerosis complex (TSC) has developed over a period of time spanning 160 years has come form simple clinical observations, pathological studies and technological advances of imaging methods. It all began with PFO Rayer's color plate of a drawing of a patient who apparently had facial angiofibroma, published in the year 1835, and continued with von Recklinghausen's report of cardiac myomas and cerebral sclerosis in a newborn who had died minutes after birth. The seminal contribution was provided by D.M. Bourneville who, in 1880, reported and named as tuberous sclerosis the neuropathological findings in a young patient with seizures, hemiplegia, and mental subnormality who also had renal tumors. We now know that TSC is a hamartomatosis, and thanks to studies of recent years using positional cloning and DNA analysis, we are beginning to understand the biological mechanisms of these disorders which include NF1, NF2 and von Hippel-Lindau disease. Unique to TSC is that it is both phenotypically and genotypically heterogeneous. One of two suspected genes found in chromosome 16 by positional cloning has been cloned (TSC2). Another one that was discovered earlier in chromosome 9 (TSC1) has not yet been characterized. The gene product from TSC2 has been named tuberin.
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PMID:History of the tuberous sclerosis complex. 888 73

Tuberous sclerosis (TS) is an autosomal dominant disorder in which affected individuals manifest mental retardation, seizures, and a variety of benign and malignant tumors. The TSC2 tumor suppressor gene was recently identified by positional cloning and its protein product, tuberin, shown to represent one member of the rap GTPase activating protein (rapGAP) family. In order to determine the contribution of tuberin to the development of mental retardation and seizures in patients with TS, we examined the expression of tuberin in adult and developing nervous system tissues. Since tuberin is the second rapGAP found in the nervous system, the expression of tuberin was compared to the expression of rapGAP, rap1, and rap2. In this study, we demonstrate that tuberin is expressed at greatest levels in the spinal cord and cerebellum as opposed to rapGAP, which is not enriched in these tissues. Tuberin expression in the adult CNS is restricted to the olfactory bulb, several CNS neuronal populations, brainstem nuclei, cerebellar Purkinje cells, and motor neurons in the ventral spinal cord. In contrast, rapGAP is expressed in many different cell types in the adult CNS, but not in cerebellar Purkinje cells or motor neurons in the ventral spinal cord. However, there is significant expression of rapGAP in astrocytes. The restricted distribution of tuberin expression relative to rap1 and rapGAP suggests that tuberin may be the primary rap1 regulator in a subpopulation of CNS neurons.
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PMID:Expression of the tuberous sclerosis 2 gene product, tuberin, in adult and developing nervous system tissues. 917 18

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by seizures, mental retardation, and tumors of skin, brain, heart, and kidney. In this study, we focused on two of the most frequent tumors in TSC patients, renal angiomyolipomas and subependymal giant cell astrocytomas (SEGAs). Two questions were addressed. First, is loss of tuberin, the product of the TSC2 gene, seen in both renal and central nervous system tumors from TSC patients? Second, when loss of tuberin occurs, does it affect each of the cell types seen in these tumors? We used a loss of heterozygosity approach to identify tumors from TSC2 patients. We found loss of tuberin immunostaining in the spindle and epithelioid cells but not in the giant cells of six TSC2 SEGAs. We also found loss of tuberin immunostaining in all three cell types (smooth muscle, fat, and vessels) of six TSC2 angiomyolipomas. Chromosome 16p13 loss of heterozygosity occurred in both spindle and epithelioid cells of a SEGA and in smooth muscle and fat but not the vessels of two angiomyolipomas. These results support a two-hit tumor suppressor model for the pathogenesis of SEGAs and angiomyolipomas. The vascular elements of angiomyolipomas and the giant cells of SEGAs may be reactive rather than neoplastic.
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PMID:Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two-hit model for the pathogenesis of tuberous sclerosis tumors. 940 14

Lymphangiomyomatosis (LAM) is a rare disease, of unknown etiology, affecting women almost exclusively. Lung transplantation is the only consistently effective therapy for LAM. Microscopically, LAM consists of a diffuse proliferation of smooth muscle cells. LAM can occur without evidence of other disease (referred to as "sporadic LAM") or in association with tuberous sclerosis complex (TSC). TSC is an autosomal dominant tumor suppressor gene syndrome characterized by seizures, mental retardation, and tumors in the brain, heart, skin, and kidney. Renal angiomyolipomas occur in approximately 50% of sporadic LAM patients and in 70% of TSC patients. Loss of heterozygosity (LOH) in the chromosomal region for the TSC2 gene occurs in 60% of TSC-associated angiomyolipomas. Because of the similar pulmonary and renal manifestations of TSC and sporadic LAM, we hypothesized that LAM and TSC have a common genetic basis. We analyzed renal angiomyolipomas, from 13 women with sporadic LAM, for LOH in the regions of the TSC1 (chromosome 9q34) and TSC2 (chromosome 16p13) genes. TSC2 LOH was detected in seven (54%) of the angiomyolipomas. We also found TSC2 LOH in four lymph nodes from a woman with retroperitoneal LAM. No TSC1 LOH was found. Our findings indicate that the TSC2 gene may be involved in the pathogenesis of sporadic LAM. However, genetic transmission of LAM has not been reported. Women with LAM may have low-penetrance germ-line TSC2 mutations, or they may be mosaic, with TSC2 mutations in the lung and the kidney but not in other organs.
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PMID:Evidence that lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangiomyomatosis. 952 62

Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by a mutation in either the TSC1 or TSC2 tumour suppressor gene. The disease is characterized by a broad phenotypic spectrum that can include seizures, mental retardation, renal dysfunction and dermatological abnormalities. TSC2 encodes tuberin, a putative GTPase activating protein for rap1 and rab5. The TSC1 gene was recently identified and codes for hamartin, a novel protein with no significant homology to tuberin or any other known vertebrate protein. Here, we show that hamartin and tuberin associate physically in vivo and that the interaction is mediated by predicted coiled-coil domains. Our data suggest that hamartin and tuberin function in the same complex rather than in separate pathways.
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PMID:Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. 958 Jun 71

The role of surgery in the treatment of refractory epilepsy (RE) in tuberous sclerosis complex (TSC) is poorly defined. Four patients with RE and TSC were evaluated for epilepsy surgery from 1994 to 1996. Three of four patients developed infantile spasms within 5 months of birth. These progressed to frequent complex partial and generalized tonic/myoclonic seizures refractory to antiepileptic drug therapy. Neuroimaging revealed typical findings of TSC including calcified lesions consistent with hamartomas. Clinical and EEG evidence suggested an epileptic focus near a prominent lesion in each child. This was confirmed using magnetic source imaging in 1 case. All patients underwent inpatient continuous video-EEG monitoring followed by temporal lobectomy or focal cortical resection with intraoperative EEG. Age at operation ranged from 5 to 13 years. Three out of 4 patients experienced a greater than 90% decrease in seizure activity. One patient continues to have rare complex partial seizures, and 1 has rare simple partial seizures. Tumor DNA analysis revealed mutations in the TSC1 gene in case 1 and the TSC2 gene in case 2; no mutations have been identified yet in cases 3 and 4. Temporal lobectomy and focal cortical resection can result in improved seizure control in patients with TSC and RE.
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PMID:On the surgical treatment of refractory epilepsy in tuberous sclerosis complex. 965 46

Tuberous sclerosis is a relatively common inherited disease that causes multiple benign tumours in different organs, frequently leading to skin rashes, seizures and mental handicap. The disease can be caused by mutations in either of two genes, TSC2, identified in 1993, and TSC1, only recently identified. Here we review the current state of knowledge of the molecular genetics of tuberous sclerosis and the spectrum of mutations seen in and the implications of recent findings for patients. Although both genes appear to function as tumour suppressors, the function of their protein products is not understood. A speculative model of how these proteins might function is briefly described.
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PMID:The genetic basis of tuberous sclerosis. 974 93

Tuberous sclerosis (TSC) is an autosomal dominant disorder characterised by tumour-like malformations (hamartomas) of the brain, skin, and other organs, often associated with seizures and learning disability. There is genetic heterogeneity with loci for TSC on chromosomes 9q34 (TSC1) and 16p13.3 (TSC2). The recently cloned TSC1 gene has 23 exons spanning some 40 kb of genomic DNA with an 8.6 kb transcript. We now report the results of mutation screening by SSCP and heteroduplex analysis of genomic DNA for all 21 coding exons of TSC1 in 83 unrelated cases of tuberous sclerosis. TSC1 gene mutations were found in 16 of the 83 cases (19%). These comprised base substitutions, small insertions, or small deletions giving rise to six nonsense mutations, eight frameshifts, and two splice site mutations, all of which would be expected to result in a truncated or absent protein. In the 10 cases predicted to have TSC1 mutations by linkage analysis or loss of heterozygosity studies, the mutation was identified in eight (80%). In the remaining 73 unassigned cases, only eight mutations were found (11%). From these data we estimate that TSC1 mutations accounted for 24% of the cases in this sample (and an estimated 22% of all TSC cases). This contrasts with data from linkage studies suggesting that TSC1 and TSC2 mutations account for approximately equal numbers of families.
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PMID:Mutations in the TSC1 gene account for a minority of patients with tuberous sclerosis. 986 90


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