Tuberous Sclerosis Complex

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For the first time, according to researchers, a link has been found between a structural abnormality of the brain and autism. The link was discovered by British scientists studying patients with tuberous sclerosis (TS) who were also suspected to have autism. Tuberous sclerosis is an inherited disorder that affects many parts of the body, causing lesions on the skin and in the heart, kidneys, eyes, and brain. It is also associated with mental retardation and autism. Cambridge University researchers studied 18 TS patients with suspected autism. On testing, 9 were, in fact, found to have autism -- the other 9 where found to have other psychiatric disorders. When the researchers examined the brain scans of the 18 patients, they found that 8 of them had tubers -- brain lesions commonly found in tuberous sclerosis -- in the temporal lobes. All of these 8 patients had autism. No tubers were identified in the temporal lobes of patients without autism.
Tuberous sclerosis complex is a multisystem disorder in which neurologic problems cause the greatest disability. High rates of mental retardation and autism spectrum disorders are associated with the diagnosis. Early-onset seizures and increased tuber burden are risk factors for cognitive impairment. Early-onset seizures, particularly infantile spasms, are risk factors for autism. Tubers within the temporal lobe and cerebellum are often mentioned as risk factors for autism, although the findings are inconsistent. Seizure control is important for developmental outcome and quality of life. Early behavioral assessment and therapeutic intervention, as well as seizure control, are the most effective means of promoting neurodevelopmental outcome.
Charles M. Zaroff et al
Tuberous sclerosis complex is a dominantly inherited disorder affecting multiple organs; because of its phenotypic variability, the diagnosis of tuberous sclerosis complex can be difficult in the young or in individuals with subtle findings. Recently revised consensus diagnostic criteria for tuberous sclerosis complex reflect an improved understanding of its clinical manifestations and its genetic and molecular mechanisms. The diagnostic criteria are based on the premise that there are probably no truly pathognomonic clinical signs for tuberous sclerosis complex; signs that were once regarded as specific occur as isolated findings in individuals with no other clinical or genetic evidence of tuberous sclerosis complex. Consequently, the revised criteria require tuberous sclerosis complex-associated lesions of two or more organ systems or at least two dissimilar lesions of the same organ to confirm the diagnosis.
Epilepsy is very common in tuberous sclerosis complex and occurs in 80 to 90% of affected individuals during their lifetime. Onset usually occurs during childhood, and up to one third of children with tuberous sclerosis complex will develop infantile spasms. Although not completely understood, the incidence of epilepsy is thought to relate to the neuropathologic features of the disorder, including cortical tubers and other dysgenetic features. Individuals with tuberous sclerosis complex frequently have epileptiform features to their electroencephalograms. Treatment of epilepsy in tuberous sclerosis complex is similar to epilepsy resulting from other causes and includes anticonvulsant medications, the vagus nerve stimulator, and the ketogenic diet. Vigabatrin has been shown to be particularly effective in treating infantile spasms in the setting of tuberous sclerosis complex. Epilepsy surgery has a very important role in the management of children and adults with pharmacoresistant epilepsy in tuberous sclerosis complex.
Elizabeth Anne Thiele
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 × 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.
Alistair Jones et al
A pair of monozygotic male twins with tuberous sclerosis (TS) were followed between 18 months and 3 years of age. Twin A with 25 large cortical tubers and hence extensive brain involvement was moderately mentally retarded and met criteria for autism. The other twin had more (n = 31) but smaller tubers. He was not mentally retarded and did not meet criteria for autism. This study provides evidence that nongenetic factors such as extent of brain abnormality and not just number of cortical tubers are important in determining phenotypic variability in TS. The findings also raise questions about the mechanisms giving rise to autism in TS.
A. Humphrey, J. N. Higgins, J. R. Yates, P. F. Bolton
The results indicated that individuals with tuberous sclerosis are at very high risk of developing an autism spectrum disorder when temporal lobe tubers are present and associated with temporal lobe epileptiform discharges and early-onset, persistent spasm-like seizures. These risk markers constitute useful clinical indicators of prognosis, but further research is required to identify the neurobiological mechanisms responsible for their association with outcome.
Patrick F. Bolton et al
Reviews literature of commonly associated neuropsychiatric complications, including mental retardation, autism-like features, and other behavior problems, discussed in the context of the neuropathology and epilepsy observed in TSC.
Miya Asato, Antonio Hardan
In summary, we have identified a novel missense change at a highly conserved residue within the region of GTPase activating domain homology of the TSC2 gene in two four generation TSC pedigrees with a total of more than 40 affected members. This is, to our knowledge, by far the largest known group of TSC patients carrying the same mutation.
Leena Khare et al, Journal of Medical Genetics
Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by hamartomas in one or more organs, including the brain, skin, heart and kidneys. Linkage studies have shown locus heterogeneity with one TSC gene mapped to chromosome 9q34 and a second to 16p13.3. The gene on 16p13.3, TSC2, has been cloned and shown to encode a 5.5 kb transcript that is widely expressed. To facilitate the search for mutations in the TSC2 gene product, tuberin, we have designed an RT-PCR-based assay system to scan the expressed coding region of the TSC2 gene in lymphoblasts. Using 34 overlapping PCR assays we performed single-strand conformation polymorphism analysis of DNA from 26 apparently sporadic TSC cases, two TSC families non-informative for linkage analysis and two confirmed chromosome 16-linked TSC families. Of the 60 chromosomes scanned, 14 showed abnormal SSCP mobility shifts. Using direct PCR sequencing we have identified five missense mutations, one 3 bp in-frame deletion and one 2 bp frameshift deletion, one nonsense mutation, one 29 bp tandem duplication and five silent nucleotide changes that are likely to be polymorphisms. There is no apparent clustering of mutations within TSC2. The diversity of mutation types argues that TSC2 may not act in a classic tumor suppressor fashion. In addition, we saw no specific correlation between the different mutations and clinical severity or expression. These data confirm that TSC2 is indeed the relevant gene, and that a substantial number of sporadic cases arise from mutations in the TSC2 gene.
Peter J. Wilson et al
Children with autism have an increased risk for obstetric complications but it is not known whether these are of primary aetiological significance. It is also unclear whether obstetric complications play a secondary role in shaping phenotypic expression in individuals at genetic risk for autism. We investigated this question by studying the role of obstetric complications in determining phenotypic manifestations in tuberous sclerosis, a single gene disorder frequently associated with autism spectrum disorders. Obstetric histories of 43 children with non-familial TS and 40 unaffected siblings were obtained using a structured parent interview. ADI-R, ADOS-G and IQ evaluations were undertaken. Children with TS experienced more obstetric complications than their unaffected siblings, but these were related to mild rather than severe adversities. No differences in obstetric complications were found in children with and without autism spectrum disorders and there was no positive correlation between obstetric adversities and severity of autism spectrum disorders or intellectual impairments.
Rebecca J. Park, Patrick Bolton
Tuberous sclerosis complex is associated with radiologically visible abnormalities of brain structure, principally tubers and subependymal nodules. We reviewed the literature on neuroimaging of tubers and subependymal nodules and found qualitative evidence of bilateral, predominantly frontal distribution of tubers and bilateral, predominantly subcortical distribution of subependymal nodules in prior studies of pediatric samples.
Khanum Ridler et al
There has been increasing awareness that there are behavioral phenotypes in tuberous sclerosis complex with neuropsychiatric symptom complex such as autistic disorder and attention-deficit hyperactivity disorder (ADHD). However, the neurobiologic basis of autistic disorder in tuberous sclerosis complex is still unknown. We studied two cohorts of children followed up since 1986 until 2003, one cohort with tuberous sclerosis complex and another cohort with autistic disorder, to determine the incidence of autistic disorder in tuberous sclerosis complex and the incidence of tuberous sclerosis complex in autistic disorder respectively. We established a Tuberous Sclerosis Complex Registry in 1985 at the University of Hong Kong. In 2004, 44 index cases (the male to female ratio was 0.75:1) were registered. Three had a positive family history of tuberous sclerosis complex. Thus, the total number of tuberous sclerosis complex cases was 47. We adopted the diagnostic criteria of tuberous sclerosis complex for case ascertainment. The period prevalence rate of tuberous sclerosis complex for children and adolescents aged = 20 years is 3.5 per 10,000 (on Hong Kong island, excluding the eastern region with 125,100 aged = 20 years in 2003). Of 44 cases with tuberous sclerosis complex, 7 had autistic disorder. Thus, the incidence of autistic disorder in tuberous sclerosis complex is 16%. During the 17-year period (1986-2003), we collected a database of 753 children (668 boys and 84 girls; male to female ratio 8:1) with autistic disorder and pervasive developmental disorders. For all children with autistic disorder or pervasive developmental disorders, we routinely examined for any features of tuberous sclerosis complex by looking for neurocutaneous markers such as depigmented spots, which appear in 50% of children with tuberous sclerosis complex by the age of 2 years. For those with infantile spasm or epilepsy, the clinical features of tuberous sclerosis complex were monitored regularly during follow-up. Of these, seven had tuberous sclerosis complex. Thus, the incidence of tuberous sclerosis complex in autistic disorder is 0.9%. All of these children are mentally retarded, with moderate to severe grades in an intellectual assessment conducted by a clinical psychologist. Future studies should be directed toward looking at the various behavioral phenotypes in tuberous sclerosis complex and defining these with standardized criteria to look for any real association with the underlying genetic mutation of TSC1 or TSC2 gene or even the site of tubers in the brain.
Virginia Wong, Medscape
It seems that somewhere between a quarter to a half of children with tuberous sclerosis develop an autism spectrum disorder. The rate of autism spectrum disorders in the general population is substantially lower (around 0.5 or 0.6%) so there is clearly a very substantial increase in the rate in children with tuberous sclerosis. Likewise, the rate of tuberous sclerosis in children diagnosed as suffering from an autism spectrum disorder is around 1%. Although this is a relatively low rate it is still clearly much higher than the rate of tuberous sclerosis in the general population, which is somewhere between 1 in 10,000 to 1 in 20,000 individuals. Either way, therefore, the overlap between autism spectrum disorders and tuberous sclerosis is very clear.
Patrick Bolton
Tuberous sclerosis complex is an autosomal dominant disorder that causes significant complications in multiple organ systems. TSC causes abnormal cellular differentiation and proliferation along with abnormal neuronal migration.
Steven P. Sparagana, E. Steve Roach
This study suggests that with appropriate and rigorous antiepileptic drug treatment, most children with WS caused by TSC can achieve a 50% or greater reduction in seizure frequency, despite severe mental retardation.
Aatif M. Husain, Catherine M. Foley, Agustin Legido, Darryl A. Chandler, Daniel K. Miles, Warren D. Grover

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