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Results for “SCLEROSIS, TUBEROUS”

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PubMed2005

Successful live related renal transplant in a case of tuberous sclerosis.

Tuberous sclerosis (TS) is an autosomal dominant multisystemic disease involving primarily the skin, the brain and the kidneys. Inspite of the kidney being involved in 40-80% of patients with this disease, the incidence of end stage renal disease is only about 1%. There are only 34 reported cases of successful renal transplantation in tuberous sclerosis patients with end stage renal disease. We report a case of successful renal transplantation in a patient of tuberous sclerosis with bilateral polycystic kidneys presenting with renal failure who also underwent bilateral native nephrectomies on follow up.

Adult↗

PubMed2004

Neuroepileptic correlates of autistic symptomatology in tuberous sclerosis.

Tuberous sclerosis is a genetic condition that is strongly associated with the development of an autism spectrum disorder. However, there is marked variability in expression, and only a subset of children with tuberous sclerosis develop autism spectrum disorder. Clarification of the mechanisms that underlie the association and variability in expression will potentially throw light on the biological processes involved in the etiology of idiopathic forms of autism spectrum disorder. Current evidence indicates that the likelihood of a child with tuberous sclerosis developing an autism spectrum disorder is greater if the child has a mutation in the TSC2 gene, although autism can and does develop in children with TSC1 mutations. The likelihood is also greater if the child has early-onset infantile spasms that are difficult to control, especially if there is an epileptiform focus in the temporal lobes. The emerging evidence is consistent with the notion that early onset electrophysiological disturbances within the temporal lobes (and perhaps other locations) has a deleterious effect on the development and establishment of key social cognitive representations concerned with processing social information, perhaps especially from faces. However, alternative mechanisms to account for the findings cannot yet be ruled out. Future research will have to employ prospective longitudinal designs and treatment trials to clarify the processes involved.

Autistic Disorder↗

PubMed1996

[Arterial fibromuscular dysplasia and Bourneville's tuberous sclerosis].

Tuberous sclerosis is an autosomal dominant disease characterized by the development of multiple hamartomas which involve mainly the skin, the brain, the kidneys, and the heart. Vascular involvement is uncommon, with essentially several reports of aortic aneurysm. The present case concerns a two and a half year-old girl with known tuberous sclerosis, who underwent a graft replacement of an abdominal aortic aneurysm revealed by hypertension, associated with a right nephrectomy for multiple renal angiomyolipomas and cysts. Microscopic examination of the aortic aneurysm and the right renal artery showed fibromuscular dysplasia. This case and the rare previous reports emphasize the possible vascular involvement in tuberous sclerosis, and suggest that arterial fibromuscular dysplasia may represent an additional manifestation of the disease.

Aortic Aneurysm↗

PubMedDate not supplied

Tuberous sclerosis.

Tuberous sclerosis is a multisystem disorder of autosomal dominant inheritance that has important eye signs which contribute substantially to the diagnosis. The disease has been recognized for over 100 years, classically by the occurrence of the triad of mental retardation, epilepsy and adenoma sebaceum of the face. Children with tuberous sclerosis often present with infantile spasms. Eye manifestations include retinal phakomata which may be granular, white and calcified, or flat, translucent and noncalcified. Additional findings include angiofibromas of the lids, poliosis, retinal and iris depigmentation, and atypical colobomata. Various systemic and ocular signs of tuberous sclerosis may develop over the years. For purposes of both patient management and genetic counselling, diagnosis based on early signs is important. The ophthalmologist may play an important role in this regard, as the characteristic phakomata can often be detected within the first two years of life.

Adolescent↗

PubMed1998

Mutations in the TSC1 gene account for a minority of patients with tuberous sclerosis.

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.

Genetic Linkage↗

PubMed2006

Tuberous sclerosis.

Tuberous sclerosis is a serious inherited disease which poses major challenges for affected families and those caring for them. Identification of the genes causing the condition and study of their protein products has shed light on the pathogenesis of the disease and provided valuable new information about signalling pathways regulating protein synthesis and cell growth. There is now the exciting possibility of drug therapy for some of the manifestations of the disease.

Adult↗

PubMed2000

Simultaneous loss of hamartin and tuberin from the cerebrum, kidney and heart with tuberous sclerosis.

Tuberous sclerosis (TSC) is caused by a mutation in either the TSC1 or TSC2 gene. The clinical manifestations of mutations of the two genes are hardly distinguishable, for reasons as yet unknown. In this study, we examined the expression of the products of these genes, hamartin and tuberin, in control and TSC tissues. Western blotting disclosed that hamartin and tuberin are both abundant in the cerebral gray matter and that they have similar subcellular distributions and developmental patterns of expression. Immunohistochemical localizations of hamartin and tuberin were also similar, with high levels of expression being localized to the cerebral neurons and glial cells, renal uriniferous and collecting tubules, and cardiac muscles. In the cerebrum with TSC, both hamartin and tuberin were simultaneously reduced in the cortical tubers and subependymal giant cell astrocytomas, and from the normal-appearing cortex. The renal angiomyolipomas and cardiac rhabdomyomas also showed a loss of both the proteins. These results provide evidence for the co-localization and interaction of hamartin and tuberin in vivo, and suggest that a mutation in one TSC gene may secondarily affect the expression of the other in some TSC lesions.

Adolescent↗

PubMed2000

[Tuberous sclerosis].

Tuberous sclerosis is an autosomal dominant disorder in which patients develop hamartomatous lesions in many different organs, most commonly in the brain, heart, kidney and skin. Two TSC-determining loci have been mapped to chromosomes 9q34 (TSC1) and to 16p13.3 (TSC2). These genes act as tumor suppressor genes, but the mechanism of hamartomatous growth is not completely understood. Recently, the prevalence of TSC is increased by new developments such as the imaging techniques. However, in some cases, physicians were not able to diagnose some TSC individuals because they were asymptomatic or because their symptoms or signs were various. In this review, we present the clinical features and molecular analysis.

Chromosomes, Human, Pair 16↗

PubMed2003

The cell cycle and tuberous sclerosis.

Tuberous sclerosis (TSC) is an autosomal dominant tumor suppressor gene syndrome occurring in about 1 in 6000 live births. Two genes have been shown to be responsible for this disease: TSC1 on chromosome 9q34, encoding hamartin, and TSC2 on chromosome 16p13.3, encoding tuberin. Although several different functions of these proteins have been described, the molecular mechanism for the development of TSC remains elusive. Mammalian and Drosophila TSC genes have been shown to be involved in cell cycle regulation. The Drosophila TSC genes have further been demonstrated to affect cell size control and to be related to the insulin signaling pathway. Very recent data provide evidence that mammalian TSC genes are also involved in cell size regulation.

Animals↗

PubMed2001

Denaturing high-performance liquid chromatography (DHPLC)-based prenatal diagnosis for tuberous sclerosis.

Tuberous sclerosis (TSC) is a frequent autosomal-dominant condition (affecting 1 in 6000 individuals) caused by various mutations in either the hamartin (TSC1) or the tuberin gene (TSC2). This allelic and non-allelic heterogeneity makes genetic counseling and prenatal diagnosis difficult, especially as a significant proportion of TSC cases are due to de novo mutations. For this reason the identification of the disease causing mutation is mandatory for accurate counseling, yet current mutation detection methods such as single-strand conformation polymorphism (SSCP) or denaturing gradient gel electrophoresis (DGGE) are labor intensive with limited detection efficiency. Denaturing high-performance liquid chromatography (DHPLC) is a high-throughput, semi-automated mutation detection system with a reported mutation detection rate close to 100% for PCR fragments of up to 800 bp. We used a recently described DHPLC assay allowing the efficient detection of mutations in TSC1 to analyze the DNA extracted from a chorion villus sample in order to perform a prenatal diagnosis for TSC. The fetus was found not to have inherited the deleterious mutation and the DHPLC diagnosis was confirmed by haplotype analysis. This represents the first DHPLC-based prenatal diagnosis of a genetic disease.

Chorionic Villi↗

PubMed1997

Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis.

Tuberous sclerosis (TSC) is an autosomal dominant disorder characterised by the development of hamartomatous growths in many organs. Sixty to seventy percent of cases are sporadic and appear to represent new mutations. TSC exhibits locus heterogeneity: the TSC2 gene is located at 16p13.3 whilst the TSC1 gene, predicted to encode a novel protein termed hamartin, has recently been cloned from 9q34. With the exception of a contiguous gene deletion syndrome involving TSC2 and PKD1 , TSC1 and TSC2 phenotypes have been considered identical. We have now comprehensively defined the TSC1 mutational spectrum in 171 sequentially ascertained, unrelated TSC patients by single strand conformation polymorphism and heteroduplex analysis of all 21 coding exons, and by assaying a restriction fragment spanning the whole locus. Mutations were identified in 9/24 familial cases, but in only 13/147 sporadic cases. In contrast, a limited screen revealed TSC2 mutations in two of the familial cases and in 45 of the sporadic cases. Thus TSC1 mutations were significantly under-represented among sporadic cases (Fisher's exact p -value = 3.12 x 10(-4)). Both large deletions and missense mutations were common at the TSC2 locus whereas most TSC1 mutations were small truncating lesions. Mental retardation was significantly less frequent among carriers of TSC1 than TSC2 mutations (odds ratio 5.54 for sporadic cases only, 6.78 +/- 1.54 when a single randomly selected patient per multigeneration family was also included). No correlation between mental retardation and the type of mutation was found. We conclude that there is a reduced risk of mental retardation in TSC1 as opposed to TSC2 disease and that consequent ascertainment bias, at least in part, explains the relative paucity of TSC1 mutations in sporadic TSC.

Humans↗

PubMed1999

Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of multiple hamartomas involving many organs. About two-thirds of the cases are sporadic and appear to represent new mutations. With the cloning of two causative genes, TSC1 and TSC2 it is now possible to analyze both genes in TSC patients and identify germline mutations. Here we report the mutational analysis of the entire coding region of both TSC1 and TSC2 genes in 126 unrelated TSC patients, including 40 familial and 86 sporadic cases, by single-stranded conformational polymorphism (SSCP) analysis followed by direct sequencing. Mutations were identified in a total of 74 (59%) cases, including 16 TSC1 mutations (5 sporadic and 11 familial cases) and 58 TSC2 mutations (42 sporadic and 16 familial cases). Overall, significantly more TSC2 mutations were found in our population, with a relatively equal distribution of mutations between TSC1 and TSC2 among the familial cases, but a marked underrepresentation of TSC1 mutations among the sporadic cases (P = 0.0035, Fisher's exact test). All TSC1 mutations were predicted to be protein truncating. However, in TSC2 13 missense mutations were found, five clustering in the GAP-related domain and three others occurring in exon 16. Upon comparison of clinical manifestations, including the incidence of intellectual disability, we could not find any observable differences between TSC1 and TSC2 patients. Our data help define the distribution and spectrum of mutations associated with the TSC loci and will be useful for both understanding the function of these genes as well as genetic counseling in patients with the disease.

Codon, Nonsense↗

PubMed1999

Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis.

Tuberous sclerosis (TSC [MIM 191090 and MIM 191100]) is an autosomal dominant disorder characterized by hamartomas in many organs. Two thirds of cases are sporadic and are thought to represent new mutations. TSC is caused by mutations affecting either of the presumed tumor-suppressor genes, TSC1 and TSC2. Both appear to function as tumor suppressors, because somatic loss or intragenic mutation of the corresponding wild-type allele is seen in the associated hamartomas. Here we report the first comprehensive mutation analysis of TSC1 and TSC2 in a cohort of 150 unrelated TSC patients and their families, using heteroduplex and SSCP analysis of all coding exons and using pulsed-field gel electrophoresis and conventional Southern blot analysis and long PCR to screen for large rearrangements. Mutations were characterized in 120 (80%) of the 150 cases, affecting TSC1 in 22 cases and TSC2 in 98 cases. TSC1 mutations were significantly underrepresented in sporadic cases (P=. 000185). Twenty-two patients had TSC2 missense mutations that were found predominantly in the GAP-related domain (eight cases) and in a small region encoded in exons 16 and 17, between nucleotides 1849 and 1859 (eight cases), consistent with the presence of residues performing key functions at these sites. In contrast, all TSC1 mutations were predicted to be truncating, consistent with a structural or adapter role for the encoded protein. Intellectual disability was significantly more frequent in TSC2 sporadic cases than in TSC1 sporadic cases (P=.0145). These data provide the first representative picture of the distribution and spectrum of mutations across the TSC1 and TSC2 loci in clinically ascertained TSC and support a difference in severity of TSC1- and TSC2-associated disease.

Blotting, Southern↗

PubMed2004

Spectrum of epilepsy in tuberous sclerosis.

Tuberous sclerosis (TS) is an autosomal dominant disease that affects the brain, skin, eye, heart and kidney. The diagnostic criteria for tuberous sclerosis complex (TSC) have recently been revised. There are relatively few Indian studies on this disorder. Twenty-six patients diagnosed as having TS over a period of 18 years are being reported. The onset of seizures ranged from infancy to adolescence. The patterns of epilepsy encountered were generalized tonic clonic seizures (13), complex partial seizures (10), simple partial seizures (9) and myoclonic jerks (4) including infantile spasms (3). Patients often had more than one seizure type. Nineteen patients were mentally subnormal. Cutaneous manifestations were facial angiofibroma i.e. adenoma sebaceum (20), shagreen patches (7), hypopigmented macules (6), ash leaf spots (4), café-au-lait spots (2), facial hypoplasia (2) and periungual fibromas (1). One patient each had retinal phakoma and renal angiomyolipoma. CT scan revealed sub-ependymal calcifications (12), parenchymal tubers (3), cerebral edema (3) and cortical atrophy (1). One patient had enhancement of peri-ventricular sub-ependymal lesions on MRI. Anticonvulsants prescribed were phenobarbitone (20), diphenyl hydantoin (14), carbamazepine (8), sodium valproate (4), benzodiazepines (4), ACTH (2), prednisone (1), mysoline (1) and vigabatrin (1). Most patients were on combinations of anti-convulsants and response to therapy was usually not very satisfactory. However, the child treated with vigabatrin did well.

Adolescent↗

PubMed2000

[Partial seizures in a newborn with tuberous sclerosis].

Tuberous sclerosis is characterized by the potential for hamartomatous growth in multiple organs. Common manifestations are hypomelanotic spots, facial angiofibromas, subependymal hamartomas, cortical tubers, cardiac rhabdomyomas, retinal hamartomas, and so on. Seizures and mental retardation are frequent. It is an autosomal dominant disease but there is a high percentage of spontaneous mutations. Neonatal diagnosis is exceptional. We report a case of a female term newborn who presented partial motor seizures at the third day of life. Physical examination revealed only a disturbance of cardiac rhythm. Echocardiography showed ventricular intramural rhabdomyomas. Magnetic resonance imaging disclosed periventricular subependymal nodules and cortical tubers. A retinal hamartoma was found in the right eye. At the age of 1 month, hypomelanotic spots were evident on the back skin. The patient had infantile spasms, followed by poorly controlled partial complex seizures together with severe psychomotor retardation. Examination of both parents was normal. We discuss the uncommon diagnosis of tuberous sclerosis during the neonatal period, as well as the exceptional mode of presentation of our patient, with seizures in the early neonatal period, a phenomenon rarely reported in the literature.

Female↗

PubMed1987

Tuberous sclerosis.

Tuberous sclerosis is a multisystem disorder characterized by changes primarily involving the skin, eye, and central nervous system. Although the disease often produces mental retardation and seizures, this is not universal, and some patients with tuberous sclerosis lead a relatively normal life.

Diagnosis, Differential↗

PubMed2004

Morphology of cerebral lesions in the Eker rat model of tuberous sclerosis.

Tuberous sclerosis (TSC) is an autosomal dominant disorder, caused by mutations of either the TSC1 or TSC2 gene. Characteristic brain pathologies (including cortical tubers and subependymal hamartomas/giant astrocytomas) are thought to cause epilepsy, as well as other neurological dysfunction. The Eker rat, which carries a spontaneous germline mutation of the TSC2 gene (TSC2+/-), provides a unique animal model in which to study the relationship between TSC cortical pathologies and epilepsy. In the present study, we have analyzed the seizure propensity and histopathological features of a modified Eker rat preparation, in which early postnatal irradiation was employed as a "second hit" stimulus in an attempt to exacerbate cortical malformations and increase seizure propensity. Irradiated Eker rats had a tendency toward lower seizure thresholds (latencies to flurothyl-induced seizures) than seen in non-irradiated Eker rats (significant difference) or irradiated wild-type rats (non-significant difference). The majority of irradiated Eker rats exhibited dysplastic cytomegalic neurons and giant astrocyte-like cells, similar to cytopathologies observed in TSC lesions of patients. The most prominent features in these brains were hamartoma-like lesions involving large eosinophilic cells, similar to giant tuber cells in human TSC. In some cells from these hamartomas, immunocytochemistry revealed features of both neuronal and glial phenotypes, suggesting an undifferentiated or immature cell population. Both normal-appearing and dysmorphic neurons, as well as cells in the hamartomas, exhibited immunopositivity for tuberin, the protein product of the TSC2 gene.

Animals↗

PubMedDate not supplied

[Tuberous sclerosis].

Tuberous sclerosis is a rare congenital disease characterized by developmental defects of the central nervous system, skin and inner organs with the development of tumours. One case of tuberous sclerosis is described in a 45-year-old female with the involvement of the brain, eyes, skin, kidneys and lungs. The cause of death was uremia as a consequence of large kidney angiomyolipomas.

Brain↗