Low-level mosaicism in tuberous sclerosis complex: prevalence, clinical features, and risk of disease transmission

Γιαννίκου, Κρινιώ; Lasseter, Kathryn D.; Grevelink, Joannes M.; Tyburczy, Magdalena E.; Dies, Kira; Zhu, Zachary; Hamieh, Lana; Wollison, Bruce M.; Thorner, Aaron R.; Ruoss, Stephen J.; Thiele, Elizabeth A.; Şahin, Mustafa; Kwiatkowski, David J.

doi:10.1038/s41436-019-0562-6

Cited by 48 publications

(92 citation statements)

References 21 publications

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“…The stratification of mosaic TSC into subtypes corresponding to disease prognosis and severity, identified phenotypic distinctions between mosaic forms of TSC. They reported mosaic patients with; asymmetrically distributed facial angiofibromas, bilaterally symmetric facial angiofibromas, and germline TSC, involving both cutaneous and internal organs [186,195,196]. Some neonates are characterized by cardiac failure due to intracardiac rhabdomyomas, and often can show an age-dependent increase in the likelihood of developing renal angiomyolipomas.…”

Section: Cutaneous Cancers Associated With Dysregulation Of the Pimentioning

confidence: 99%

Role and Therapeutic Targeting of the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic Agents Therapy

Chamcheu

Roy

Uddin

et al. 2019

Cells

136

122

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The mammalian or mechanistic target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) pathways regulate cell growth, differentiation, migration, and survival, as well as angiogenesis and metabolism. Dysregulation of these pathways is frequently associated with genetic/epigenetic alterations and predicts poor treatment outcomes in a variety of human cancers including cutaneous malignancies like melanoma and non-melanoma skin cancers. Recently, the enhanced understanding of the molecular and genetic basis of skin dysfunction in patients with skin cancers has provided a strong basis for the development of novel therapeutic strategies for these obdurate groups of skin cancers. This review summarizes recent advances in the roles of PI3K/Akt/mTOR and their targets in the development and progression of a broad spectrum of cutaneous cancers and discusses the current progress in preclinical and clinical studies for the development of PI3K/Akt/mTOR targeted therapies with nutraceuticals and synthetic small molecule inhibitors.

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Section: Cutaneous Cancers Associated With Dysregulation Of the Pimentioning

confidence: 99%

Role and Therapeutic Targeting of the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic Agents Therapy

Chamcheu

Roy

Uddin

et al. 2019

Cells

136

122

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“…Sporadic TSC can also arise when a mutation occurs early in development in a stem cell that can give rise to many tissues. This is exemplified by the extreme case of TSC patients with somatic mosaicism (Tyburczy et al, 2015 ; Giannikou et al, 2019 ). The mutation of the second allele then is proposed to occur later in development within discrete cells ( Figure 2D ).…”

Section: The Molecular Genetics Of Tscmentioning

confidence: 99%

The Neurodevelopmental Pathogenesis of Tuberous Sclerosis Complex (TSC)

Feliciano

2020

Front. Neuroanat.

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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.

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“…1,2 Past and recent studies have shown that mosaicism is relatively common in TSC, seen in 10-15% of patients, and is associated with a milder phenotype in multiple respects. [6][7][8][9][10][11] TSC1 pathogenic variants have also been associated with a milder phenotype than TSC2 pathogenic variants in multiple past reports. [12][13][14][15][16][17] EPISTOP was a long-term, prospective study assessing clinical and molecular biomarkers of epileptogenesis in TSC, which included a randomized trial of early intervention with vigabatrin in those infants in whom a high risk of seizure development was expected (NCT02098759).…”

Section: Introductionmentioning

confidence: 99%

TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: results of the EPISTOP study

Ogórek¹,

Hamieh²,

Hulshof

et al. 2020

Genetics in Medicine

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Purpose: To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations. Methods: Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. Targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection in TSC1/TSC2. Results: Pathogenic variants in TSC1 or TSC2 were identified in 93 of 94 (99%) subjects, with 23 in TSC1 and 70 in TSC2. Nine (10%) subjects had mosaicism. Eight of 24 clinical features assessed at age 2 years were significantly less frequent in those with TSC1 versus TSC2 variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizurefree survival. Additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume for TSC1 versus TSC2. Conclusion: TSC2 pathogenic variants are associated with a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in TSC infants. Early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.

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Low-level mosaicism in tuberous sclerosis complex: prevalence, clinical features, and risk of disease transmission

Cited by 48 publications

References 21 publications

Role and Therapeutic Targeting of the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic Agents Therapy

Role and Therapeutic Targeting of the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic Agents Therapy

The Neurodevelopmental Pathogenesis of Tuberous Sclerosis Complex (TSC)

TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: results of the EPISTOP study

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