Somatic double-hit in MTOR and RPS6 in hemimegalencephaly with intractable epilepsy

Pelorosso, Cristiana; Watrin, Françoise; Conti, Valerio; Buhler, Emmanuelle; Gelot, Antoinette; Yang, Xiaoxu; Mei, Davide; McEvoy‐Venneri, Jennifer; Manent, Jean-Bernard; Cetica, Valentina; Ball, Laurel; Buccoliero, Anna Maria; Vinck, Antonin; Barba, Carmen; Gleeson, Joseph G.; Guerrini, Renzo; Represa, Alfonso

doi:10.1093/hmg/ddz194

Cited by 47 publications

(55 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Incidentally, the role of signals that regulate hamartin and tuberin activity as well as the mTORC1 substrates responsible for specific developmental events are only now being determined. Perhaps most striking is the fact that somatic mutations that cause mTORC1 pathway activation have been identified as a cause of a plethora of neurological diseases (Lee et al, 2012 ; Poduri et al, 2012 ; Parker et al, 2013 ; Lal et al, 2014 ; Baek et al, 2015 ; Baulac et al, 2015 ; Crino, 2015 ; D’Gama et al, 2015 , 2017 ; Leventer et al, 2015 ; Lim et al, 2015 ; Baulac, 2016 ; Korenke et al, 2016 ; Møller et al, 2016 ; Hanai et al, 2017 ; Park et al, 2018 ; Iffland and Crino, 2019 ; Kim et al, 2019 ; Pelorosso et al, 2019 ; Salinas et al, 2019 ; Zhao et al, 2019 ; Garcia et al, 2020 ). Thus, what has been learned by studying the TSC pathway may now be applied to an expanding number of patients.…”

Section: The Molecular Genetics Of Tscmentioning

confidence: 99%

The Neurodevelopmental Pathogenesis of Tuberous Sclerosis Complex (TSC)

Feliciano

2020

Front. Neuroanat.

View full text Add to dashboard Cite

Tuberous sclerosis complex (TSC) is a model disorder for understanding brain development because the genes that cause TSC are known, many downstream molecular pathways have been identified, and the resulting perturbations of cellular events are established. TSC, therefore, provides an intellectual framework to understand the molecular and biochemical pathways that orchestrate normal brain development. The TSC1 and TSC2 genes encode Hamartin and Tuberin which form a GTPase activating protein (GAP) complex. Inactivating mutations in TSC genes (TSC1/TSC2) cause sustained Ras homologue enriched in brain (RHEB) activation of the mammalian isoform of the target of rapamycin complex 1 (mTORC1). TOR is a protein kinase that regulates cell size in many organisms throughout nature. mTORC1 inhibits catabolic processes including autophagy and activates anabolic processes including mRNA translation. mTORC1 regulation is achieved through two main upstream mechanisms. The first mechanism is regulation by growth factor signaling. The second mechanism is regulation by amino acids. Gene mutations that cause too much or too little mTORC1 activity lead to a spectrum of neuroanatomical changes ranging from altered brain size (micro and macrocephaly) to cortical malformations to Type I neoplasias. Because somatic mutations often underlie these changes, the timing, and location of mutation results in focal brain malformations. These mutations, therefore, provide gainof-function and loss-of-function changes that are a powerful tool to assess the events that have gone awry during development and to determine their functional physiological consequences. Knowledge about the TSC-mTORC1 pathway has allowed scientists to predict which upstream and downstream mutations should cause commensurate neuroanatomical changes. Indeed, many of these predictions have now been clinically validated. A description of clinical imaging and histochemical findings is provided in relation to laboratory models of TSC that will allow the reader to appreciate how human pathology can provide an understanding of the fundamental mechanisms of development.

show abstract

Section: The Molecular Genetics Of Tscmentioning

confidence: 99%

The Neurodevelopmental Pathogenesis of Tuberous Sclerosis Complex (TSC)

Feliciano

2020

Front. Neuroanat.

View full text Add to dashboard Cite

show abstract

“…We had previously demonstrated how a somatic MTOR mutation in the dysplastic hemisphere and a systemic mosaic RPS6 mutation synergistically concurred in determining a HME/epilepsy phenotype in which seizure onset had occurred in the seemingly intact hemisphere after hemispherectomy. 20 We could not exclude, however, that the MTOR mutation was also present, albeit with lower AAF ratios, in the nondysplastic hemisphere.…”

Section: Discussionmentioning

confidence: 88%

“…For patient 3, we analyzed DNA from multiple tissues sampled at autopsy, including cerebral hemispheres, cerebellum, multiple lipomas, spleen, liver, heart, and blood. We performed an mTOR genes panel analysis according to our previously published protocol 20 and confirmed the percentage of mosaicism in the different tissues using the GS Junior amplicon sequencing-based approach. 3 …”

Section: Methodsmentioning

confidence: 99%

Is Focal Cortical Dysplasia/Epilepsy Caused by Somatic MTOR Mutations Always a Unilateral Disorder?

et al. 2021

Self Cite

View full text Add to dashboard Cite

ObjectiveTo alert about the wide margin of unpredictability that distribution of somatic MTOR mosaicism may have in the brain and the risk for independent epileptogenesis arising from the seemingly healthy contralateral hemisphere after complete removal of epileptogenic focal cortical dysplasia (FCD).MethodsClinical, EEG, MRI, histopathology, and molecular genetics in 2 patients (1 and 2) treated with focal resections and subsequent complete hemispherectomy for epileptogenic FCD due to somatic MTOR mutations. Autoptic brain study of bilateral asymmetric hemispheric dysplasia and identification of alternative allele fraction (AAF) rates for AKT1 (patient 3).ResultsThe strongly hyperactivating p.Ser2215Phe (patient 1) and p.Leu1460Pro (patient 2) MTOR mutations were at low-level AAF in the dysplastic tissue. After repeated resections and eventual complete hemispherectomy, both patients manifested intractable seizures arising from the contralateral, seemingly healthy hemisphere. In patient 3, the p.Glu17Lys AKT1 mutation exhibited random distribution and AAF rates in different tissues with double levels in the more severely dysplastic cerebral hemisphere.ConclusionsOur understanding of the distribution of somatic mutations in the brain in relation to the type of malformation and its hypothesized time of origin may be faulty. Large studies may reveal that the risk of a first surgery being disappointing might be related more to the specific somatic mammalian target of rapamycin mutation identified than to completeness of resection and that the advantages of repeated resections after a first unsuccessful operation should be weighed against the risk of the contralateral hemisphere becoming in turn epileptogenic.

show abstract

“…Another possibility is that intralesional heterogeneity for mTOR/S6 pathway, which has been already described in epilepsy, could determine a wider genetic panel influenced by the area analyzed and type of mutations present on each patient. The presence of multiple mutations that have synergetic effects can be the cause for the wide spectrum of clinical features and successful surgical rates on patients with similar MCD [14].…”

Section: Discussion/conclusionmentioning

confidence: 99%

Phosphorylation of S6 Protein as a Potential Biomarker in Surgically Treated Refractory Epilepsy

et al. 2020

View full text Add to dashboard Cite

The tuberous sclerosis complex (TSC), focal cortical dysplasia IIB (FCD IIB), and hemimegalencephaly (HME) exhibit similar molecular features that are dependent on the hyperactivation of the mTOR pathway. They are all associated with refractory epilepsy and the need for surgical resection with varying outcomes. The phosphorylated protein S6 (pS6) is a downstream target of mTOR, whose increased expression might indicate mTOR hyperactivation, but which is also present when there is no alteration in the pathway (such as in FCD type I). We have performed immunohistochemical marking and quantification of pS6 in resected brain specimens of 26 patients clinically and histologically diagnosed with TSC, FCD IIB, or HME and compared this data to a control group of 25 patients, to measure the extent of pS6 positivity and its correlation with clinical aspects. Our results suggest that pS6 may serve as a reliable biomarker in epilepsy and that a greater percentage of pS6 marking can relate to more severe forms of mTOR-dependent brain anomalies.

show abstract

Somatic double-hit in MTOR and RPS6 in hemimegalencephaly with intractable epilepsy

Cited by 47 publications

References 29 publications

The Neurodevelopmental Pathogenesis of Tuberous Sclerosis Complex (TSC)

The Neurodevelopmental Pathogenesis of Tuberous Sclerosis Complex (TSC)

Is Focal Cortical Dysplasia/Epilepsy Caused by Somatic MTOR Mutations Always a Unilateral Disorder?

Phosphorylation of S6 Protein as a Potential Biomarker in Surgically Treated Refractory Epilepsy

Contact Info

Product

Resources

About