Subependymal nodules and giant cell tumours in tuberous sclerosis complex patients: prevalence on MRI in relation to gene mutation

Michelozzi, Caterina; Leo, Giovanni Di; Galli, Federica; Barbosa, Fabiane Silva; Labriola, Flavio; Sardanelli, Francesco; Cornalba, Gianpaolo

doi:10.1007/s00381-012-1892-8

Cited by 15 publications

(7 citation statements)

References 25 publications

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“…Nonetheless, the numbers of abnormalities identified in our cohort were mostly similar or higher than those reported in previous studies. 9,10,24 The number of RMLs in our cohort was lower than that reported in another cohort, possibly because we did not use diffusion tensor imaging or three-directional scans. 32 In summary, we compared TSC brain pathology to genotype.…”

Section: Discussioncontrasting

confidence: 38%

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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: Discussioncontrasting

confidence: 38%

“…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. 24 Two patients in our cohort were mosaic. Both had bilateral TSCrelated abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Genotype and brain pathology phenotype in children with tuberous sclerosis complex

et al. 2016

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“…However, only IS and epilepsy are strongly associated with TSC2 mutations, whereas MR and neurocognitive impairment are linked to different types and location of TSC1 and TSC2 germline mutations, rather than to the specific gene in which the mutation occurred (van Eeghen et al, 2013). Similarly, the presence of SENs and SEGAs is not significantly associated with either gene mutation (Michelozzi et al, 2013), and variability in TSC symptoms has been reported in individuals with identical TSC mutations (Rok et al, 2005). …”

Section: Introductionmentioning

confidence: 99%

Timing of mTOR activation affects tuberous sclerosis complex neuropathology in mouse models

Magri

Cominelli

Cambiaghi³

et al. 2013

Disease Models &Amp; Mechanisms

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SUMMARYTuberous sclerosis complex (TSC) is a dominantly inherited disease with high penetrance and morbidity, and is caused by mutations in either of two genes, TSC1 or TSC2. Most affected individuals display severe neurological manifestations – such as intractable epilepsy, mental retardation and autism – that are intimately associated with peculiar CNS lesions known as cortical tubers (CTs). The existence of a significant genotype-phenotype correlation in individuals bearing mutations in either TSC1 or TSC2 is highly controversial. Similar to observations in humans, mouse modeling has suggested that a more severe phenotype is associated with mutation in Tsc2 rather than in Tsc1. However, in these mutant mice, deletion of either gene was achieved in differentiated astrocytes. Here, we report that loss of Tsc1 expression in undifferentiated radial glia cells (RGCs) early during development yields the same phenotype detected upon deletion of Tsc2 in the same cells. Indeed, the same aberrations in cortical cytoarchitecture, hippocampal disturbances and spontaneous epilepsy that have been detected in RGC-targeted Tsc2 mutants were observed in RGC-targeted Tsc1 mutant mice. Remarkably, thorough characterization of RGC-targeted Tsc1 mutants also highlighted subventricular zone (SVZ) disturbances as well as STAT3-dependent and -independent developmental-stage-specific defects in the differentiation potential of ex-vivo-derived embryonic and postnatal neural stem cells (NSCs). As such, deletion of either Tsc1 or Tsc2 induces mostly overlapping phenotypic neuropathological features when performed early during neurogenesis, thus suggesting that the timing of mTOR activation is a key event in proper neural development.

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“…SEGAs are the most common brain tumors occurring in up to 20 % of the TSC patients, usually in the first two decades of life [6, 23, 35]. They are typically located on the surface of the lateral ventricle of the brain, and thus, while growing, they extend into the lateral ventricle and can obstruct the foramen of Monro and flow of CSF, causing hydrocephalus [8, 10].…”

Section: Discussionmentioning

confidence: 99%

Congenital subependymal giant cell astrocytomas in patients with tuberous sclerosis complex

et al. 2014

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PurposeSubependymal giant cell astrocytoma (SEGA) is a brain tumor associated with tuberous sclerosis complex (TSC). It usually grows in a second decade of life, but may develop in the first months of life. The aim of this work was to establish the incidence, clinical features, and outcome of congenital SEGA in TSC patients.MethodsCohort of 452 TSC patients was reviewed to identify cases with growing or hydrocephalus producing SEGAs in the first 3 months of life. Clinical presentation, size of the tumor, growth rate, mutational analysis, treatment applied, and outcome were analyzed.ResultsTen (2.2 %) patients presented with SEGA in the first 3 months of life. All of them had documented SEGA growth and all developed hydrocephalus. In eight patients, mutational analysis was done, and in all of them, TSC2 gene mutations were identified. Mean maximum SEGA diameter at baseline was 21.8 mm. Mean SEGA growth rate observed postnatally was 2.78 mm per month and tended to be higher (5.43 mm per month) in patients with TSC2/PKD1 mutation than in other cases. Seven patients underwent SEGA surgery and surgery-related complications were observed in 57.1 % cases. One patient was successfully treated with everolimus as a primary treatment.ConclusionsCongenital SEGA develops 2.2 % of TSC patients. Patients with TSC2 mutations, and especially with TSC2/PKD1 mutations, are more prone to develop SEGA earlier in childhood and should be screened for SEGA from birth. In young infants with SEGA, both surgery and mTOR inhibitor should be considered as a treatment option.

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Subependymal nodules and giant cell tumours in tuberous sclerosis complex patients: prevalence on MRI in relation to gene mutation

Abstract: TSC patients with SENs are more likely to present with SGCT than those without SENs, in particular for TSC2 mutation carriers. The SGCT growth rate may be missed if based on the diameter instead of on the volume.

Cited by 15 publications

References 25 publications

Genotype and brain pathology phenotype in children with tuberous sclerosis complex

Genotype and brain pathology phenotype in children with tuberous sclerosis complex

Timing of mTOR activation affects tuberous sclerosis complex neuropathology in mouse models

Congenital subependymal giant cell astrocytomas in patients with tuberous sclerosis complex

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