Cyst-like tubers are associated with TSC2 and epilepsy in tuberous sclerosis complex

Chu-Shore, Catherine J.; Major, Philippe; Montenegro, Maria Augusta; Thiele, Elizabeth A.

doi:10.1212/01.wnl.0000345365.92821.86

Cited by 99 publications

(69 citation statements)

References 22 publications

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“…Patients with more temporal tubers have a higher risk of developing autistic features 21 and cystic tubers have been associated with a higher incidence of epilepsy 22 and autism spectrum disorder. 23 The larger number of calcified SENs in the TSC2 group could also be clinically relevant, as calcified SENs are more likely to develop into a SEGA.…”

Section: Discussionmentioning

confidence: 99%

Genotype and brain pathology phenotype in children with tuberous sclerosis complex

et al. 2016

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Structural brain malformations associated with Tuberous Sclerosis Complex (TSC) are related to the severity of the clinical symptoms and can be visualized by magnetic resonance imaging (MRI). Tuberous Sclerosis Complex is caused by inactivating TSC1 or TSC2 mutations. We investigated associations between TSC brain pathology and different inactivating TSC1 and TSC2 variants, and examined the potential prognostic value of subdivision of TSC2 variants based on their predicted effects on TSC2 expression. We performed genotype-phenotype associations of TSC-related brain pathology on a cohort of 64 children aged 1.4-17.9 years. Brain abnormalities were assessed using MRI. Individuals were grouped into those with an inactivating TSC1 variant and those with an inactivating TSC2 variant. The TSC2 group was subdivided into changes predicted to result in TSC2 protein expression (TSC2p) and changes predicted to prevent expression (TSC2x). The TSC2 group was associated with more and larger tubers, more radial migration lines, and more subependymal nodules than the TSC1 group. Subependymal nodules were also more likely to be calcified. Subdivision of the TSC2 group did not reveal additional, substantial differences, except for a larger number of tubers in the temporal lobe and a larger fraction of cystic tubers in the TSC2x subgroup. The severity of TSC-related brain pathology was related to the presence of an inactivating TSC2 variant. Although larger studies might find specific TSC2 variants that have prognostic value, in our cohort, subdivision of the TSC2 group did not lead to better prediction. European Journal of Human Genetics (2016) 24, 1688-1695; doi:10.1038/ejhg.2016.85; published online 13 July 2016 INTRODUCTION Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder caused by inactivating TSC1 or TSC2 variants. 1,2 Most TSC-associated lesions are thought to arise due to somatic secondhit mutations that inactivate the remaining wild-type TSC1 or TSC2 allele. The protein products of TSC1 and TSC2 form the TSC complex, that inhibits the mammalian Target of Rapamycin Complex 1 (mTORC1). 3 Loss or inactivation of the TSC complex results in constitutive activation of mTORC1, and mTORC1 inhibitors have been shown to be useful for treating hamartoma-related complications of TSC. 4,5 Our aim was to investigate genotype-phenotype associations in a well-characterized cohort of TSC individuals, focusing on the relationships between specific TSC1 and TSC2 variants and macrostructural brain lesions detected by magnetic resonance imaging (MRI), including cortical tubers, radial migration lines (RMLs), subependymal nodules (SENs) and subependymal giant cell astrocytomas (SEGAs). In most studies, inactivating TSC2 variants are associated with increased numbers of cortical tubers and a higher prevalence of SEGAs. [6][7][8][9][10][11][12][13][14] We investigated whether there was additional clinical value for subdivision of TSC2 variants, as has been described recently for cognitive function in TSC. 15 We compared TSC-rel...

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Section: Discussionmentioning

confidence: 99%

Genotype and brain pathology phenotype in children with tuberous sclerosis complex

et al. 2016

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“…Recently, however, a few case reports and studies document the dynamic nature of a small percentage of tubers. 13 One report documented 2 patients with cystlike tubers that increased in size and number with time. 13 In our cohort, 52% of cerebellar tubers changed in some manner when longitudinally studied, supporting the dynamic nature of the infratentorial tubers.…”

Section: Discussionmentioning

confidence: 99%

MRI Characterization and Longitudinal Study of Focal Cerebellar Lesions in a Young Tuberous Sclerosis Cohort

Vaughn

Hagiwara

Katz³

et al. 2012

AJNR Am J Neuroradiol

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BACKGROUND AND PURPOSE:There are few articles characterizing cerebellar lesions in patients with TSC and no published series documenting longitudinal evaluation of these lesions, to our knowledge. Recent suggestion of a correlation between autism and cerebellar lesions in patients with TSC heightens the importance of understanding these lesions. Our purpose was to characterize cerebellar lesions in a cohort of young patients with TSC with specific interest in assessing longitudinal changes.

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“…The presence of inflammatory cells/molecules [198,199] and astrogliosis [200,201] may contribute to the changes in cell morphology in tubers. Interestingly, the development of cystic changes (end-stage of degenerative changes, affecting the white matter) has been shown to be associated with a TSC2 gene mutation and with a more aggressive seizure phenotype [202,203]. More recently, three different types of tubers (type A, B, C) have been described on the basis of the magnetic resonance imaging features [204].…”

Section: Clinical and Neuropathologic Featuresmentioning

confidence: 99%

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

Aronica

Crino

2014

Neurotherapeutics

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Cyst-like tubers are associated with TSC2 and epilepsy in tuberous sclerosis complex

Abstract: Cyst-like cortical tubers are strongly associated with TSC2 gene mutation and a more aggressive seizure phenotype in patients with tuberous sclerosis complex.

Cited by 99 publications

References 22 publications

Genotype and brain pathology phenotype in children with tuberous sclerosis complex

Genotype and brain pathology phenotype in children with tuberous sclerosis complex

MRI Characterization and Longitudinal Study of Focal Cerebellar Lesions in a Young Tuberous Sclerosis Cohort

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

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