Authors: Tyburczy ME, Wang JA, Li S, Thangapazham R, Chekaluk Y, Moss J, Kwiatkowski DJ, Darling TN.
Hum Mol Genet. 2014 23:2023-9. PMCID:PMC3959815 


Tuberous sclerosis complex (TSC) is characterized by the formation of tumors in multiple organs and is caused by germline mutation in one of two tumor suppressor genes, TSC1 and TSC2. As for other tumor suppressor gene syndromes, the mechanism of somatic second-hit events in TSC tumors is unknown. We grew fibroblast-like cells from 29 TSC skin tumors from 22 TSC subjects and identified germline and second-hit mutations in TSC1/TSC2 using next-generation sequencing. Eighteen of 22 (82%) subjects had a mutation identified, and 8 of the 18 (44%) subjects were mosaic with mutant allele frequencies of 0 to 19% in normal tissue DNA. Multiple tumors were available from four patients, and in each case, second-hit mutations in TSC2 were distinct indicating they arose independently. Most remarkably, 7 (50%) of the 14 somatic point mutations were CC>TT ultraviolet 'signature' mutations, never seen as a TSC germline mutation. These occurred exclusively in facial angiofibroma tumors from sun-exposed sites. These results implicate UV-induced DNA damage as a cause of second-hit mutations and development of TSC facial angiofibromas and suggest that measures to limit UV exposure in TSC children and adults should reduce the frequency and severity of these lesions.

Authors: Liesbeth De Waele, Lieven Lagae, Djalila Mekahli

Pediatr Nephrol; DOI 10.1007/s00467-014-3027-9


Renal lesions represent the second most significant cause of morbidity and mortality in patients with tuberous sclerosis complex (TSC). Recent advances in the understanding of the pathophysiology of TSC have led to the exploration of new potential therapeutic targets. Clinical trials with mammalian
target of rapamycin (mTOR) inhibitors have demonstrated promising results for several indications, such as renal angiomyolipoma, subependymal giant cell astrocytoma, lymphangioleiomyomatosis and facial angiofibromas. Currently, there is a scarcity of natural history data and randomized, placebo-controlled clinical trials on TSC. Recently, however, recommendations for the diagnostic criteria, surveillance,
and management of TSC patients have been updated. This review focuses on these novel recommendations and highlights the need for multidisciplinary follow-up of this multi-systemic disease.


Authors: Eleonora Aronica, Peter B. Crino

Neurotherapeutics. 2014 Apr;11(2):251-68. doi: 10.1007/s13311-013-0251-0.


Structural abnormalities of the brain are increasing-ly recognized in patients with neurodevelopmental delay andintractable focal epilepsies. The access to clinically well-characterized neurosurgical material has provided a uniqueopportunity to better define the neuropathological, neuro-chemical, and molecular features of epilepsy-associated focaldevelopmental lesions. These studies help to further under-stand the epileptogenic mechanisms of these lesions.Neuropathological evaluation of surgical specimens from pa-tients with epilepsy-associated developmental lesions revealstwo major pathologies: focal cortical dysplasia and low-gradedevelopmental tumors (glioneuronal tumors). In the last fewyears there have been major advances in the recognition of awide spectrum of developmental lesions associated with aintractable epilepsy, including cortical tubers in patients withtuberous sclerosis complex and hemimegalencephaly. As anincreasing number of entities are identified, the developmentof a unified and comprehensive classification represents agreat challenge and requires continuous updates. The presentarticle reviews current knowledge of molecular pathogenesisand the pathophysiological mechanisms of epileptogenesis inthis group of developmental disorders. Both emerging neuro-pathological and basic science evidence will be analyzed,highlighting the involvement of different, but often converg-ing, pathogenetic and epileptogenic mechanisms, which maycreate the basis for new therapeutic strategies in thesedisorders.

Authors: Nataša Jovanov Milošević1, 2, Miloš Judaš1, Eleonora Aronica3,4, Ivica Kostovic1

Prog Brain Res. 2014;214:159-78. doi: 10.1016/B978-0-444-63486-3.00007-4.


The neural extracellular matrix (ECM) provides a supportive framework to differentiating cells and their processes, and regulates morphogenetic events by spatially and temporally relevant localization of signaling molecules and by direct signaling via receptor and/or co-receptor-mediated action. Embryonic and fetal human brain contains large amount and diversity of extracellular matrix components, which is especially prominent in the transient subplate zone, in the crossroads of axonal pathways, at the developing cortex-white matter interface and in the marginal zone. Perinatal and postnatal reorganization of these tissue compartments extends into the second year of life. Developmental changes in the amount and composition of the extracellular matrix (as well as changes in fibre architectonics) are significant for plastic responses to damage as well as for changes in magnetic resonance imaging (MRI) signal intensity of the fetal and early postnatal human brain.
In this chapter we discuss the expression pattern of major components of the fetal ECM of the human brain and the role they play during laminar and connectivity development in healthy brain as well as in the neurodevelopmental disorders. The aim of the chapter is to elucidate ECM-related developmental events as potential models of successful functional recovery after injury and to explore its relevance for diagnostic and therapeutic approaches.

Authors: Sadowski K. , Józwiak S. 

Journal of Epileptology, 2014; 22(2):89-98
Manuscript ID: 892079


  • Introduction. Epilepsy that is associated with neurocutaneous disorders seriously deteriorates quality of life and cognitive outcome of affected children. Recent advances in epilepsy pathophysiology raise hopes for better treatment results in this difficult group of patients.
  • Aim. The aim of this  review is  to present recent treatment recommendations as well as current research progress in the most frequent neurocutaneous disorders.
  • Material and methods. We analyzed PubMed database to select the most prominent and recent (up to 2014 year) publications on the treatment and mechanisms of epilepsy in selected neurocutaneous disorders. We aimed to  emphasize  evidence-based medicine recommendations as well as basic experimental studies dealing with molecular mechanisms of epileptogenesis.
  • Discussion and conclusions. Recent advances in disease-modifying  treatment options such as mTOR inhibitors in patients with tuberous sclerosis complex open up new perspectives for neurologists. Traditional resective surgery has still a  major role as a treatment of choice in carefully selected cases.

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