Authors: Moavero R., Bombardieri R., Marciano S., Cerminara C., Curatolo P.

J Pediatr Epilepsy, 2016;05(02):064-9


Tuberous sclerosis complex (TSC) is associated with a high rate of epilepsy, which often presents in the first month of life. An early diagnosis of TSC can allow a close electroencephalography monitoring and a prompt detection of subtle or subclinical seizures, thus guaranteeing a prompt treatment. Seizures in TSC are caused by an imbalance between excitation and inhibition, which can be considered as the final step of the genetic mutation and the subsequent overactivation of the mammalian target of rapamycin pathway. Epilepsy is often associated with cognitive and behavioral comorbidities, including learning disability, autism, and attention deficit/hyperactivity disorder. A prompt treatment of early-onset seizures is able to reduce the risk of a subsequent epileptic encephalopathy and cognitive and behavioral sequelae, but it cannot totally revert the final outcome. Treatment options for epilepsy include antiepileptic drugs, epilepsy surgery, ketogenic diet, and vagus nerve stimulation, but even after their application about two-thirds of patients still continue to present seizures. All these treatment options represent symptomatic treatment acting on seizures but not on the underlying cause of epilepsy. Mammalian target of rapamycin inhibitors represent a potential novel treatment strategy able to target the pathophysiologic mechanisms underlying epilepsy and other TSC-related manifestations.

Authors: Switon K., Kotulska K., Janusz-Kaminska A., Zmorzynska J., Jaworski J.

International Union of Biochemistry and Molecular Biology 68:12, 955-962, Dec 2016. 


Tuberous sclerosis complex (TSC) is a rare multi-system disorder, primary manifestations of which are benign tumors and lesions in various organs of the body, including the brain. TSC patients offer suffer from epilepsy, mental retardation, and autism spectrum disorders (ASD). Therefore, TSC serves as a model of epilepsy, ASD, and tumorigenesis. TSC is caused by the lack of function Tsc1-Tsc2 complex, which serves as a major cellular inhibitor of Mammalian Target of Rapamycin Complex 1 (mTORC1). mTORC1 is a kinase controlling most of anabolic processes in eukaryotic cells. Consequently, mTORC1 inhibitors, such as rapaymcin, serve as experimental or already approved drugs for several TSC symptoms. However rapalogs, although quite effective, need to be administered chronically and likely for a lifetime, since therapy discontinuation results in tumor regrowth and epilepsy recurrence. Recent studies revealed that metabolism and excitability (in the case of neurons) of cells lacking Tsc1-Tsc2 complex are changed and these features may potentially be used to treat some of TSC symptoms. In this review, we first provide basic facts about TSC and its molecular background, to next discuss the newest findings in TSC cell biology that can be used to improve existing therapies of TSC and other diseases linked to mTORC1 hyperactivation. 

Authors: Moavero R., Marciano S., Graziola F., Curatolo P.

Epilepsy Behav Case Rep. 2016 Jan 13;5:13-6. doi: 10.1016/j.ebcr.2015.12.001. eCollection 2016.


Tuberous sclerosis is associated with epilepsy in up to 85% of cases, and in 2/3, the onset is within the first year of life. An early antiepileptic treatment is crucial to minimize the consequences of epilepsy on cognition and behavior. We present a case report of a child with tuberous sclerosis who presented with infantile spasms at the age of 6 months, immediately treated with vigabatrin. Because of the presence of a subependymal giant cell astrocytoma, he also received everolimus since 18 months of age. We might wonder if an earlier treatment could have produced a better outcome; in fact, despite a targeted combined treatment, he continues to suffer from sporadic focal motor seizures, and at the age of 40 months, he presents severe developmental delay with autism-like behavior.

Authors: van Scheppingen J., Broekaart D.W.M., Scholl T., Zuidberg M.R.J., Anink J.J., Spliet W.G., van Rijen P.C., Czech T., Hainfellner J.A., Feucht M., Mühlebner A., van Vliet E.A., Aronica E.

J Neuroinflammation. 2016 Aug 26;13(1):202. doi: 10.1186/s12974-016-0662-z.


Background: The proteasome is a multisubunit enzyme complex involved in protein degradation, which is essential for many cellular processes. During inflammation, the constitutive subunits are replaced by their inducible counterparts, resulting in the formation of the immunoproteasome. 
Methods: We investigated the expression pattern of consitutive (B1, B5) and immunoproteasome (B1i, B5i) subunits using immunohistochemistry in malformations of cortical development (MCD; focal cortical dysplasia (FCD) IIa and b, cortical tubers from patients with tuberous sclerosis complex (TSC) and mild MCD (mMCD)). Glial cells in culture were used to elucidate the mechanisms regulating immunoproteasome subunit expression. 
Results: Increased expression was observed in both FCDII and TSC; B1, B1i, B5 and B5i were detected (within cytosol and nucleus) in dysmorphic neurons, balloon/giant cells, and reactive astrocytes. Glial and neuronal nuclear expression positively correlated with seizure frequency. Positive correlation was also observed between the glial expression of constitutive and immunoproteasome subunits and IL-1B. Accordingly, the proteasome subunit expression was modulated by IL-1B in human astrocyrtes in vitro. Expression of both constitutive and immunoproteasome subunits in FCD II-derived astroglial cultures was negatively regulated by treatment with the immunomodulatory drug rapamycin (inhibitor of the mammalian target of rapamycin (mTOR) pathway, which is activated in both TSC and FCD II).
Conclusions: These observations support the dysregulation of the proteasome system in both FCD and TSC and provide new insights on the mechanism of regulation the (immuno)proteasome in astrocytes and the molecular links between inflammation, mTOR activation and epilepsy. 


Authors: Mühlebner A., van Scheppingen J., Hulshof H.M., Scholl T., Iyer A.M., Aninck J.J., van den Ouweland A.M.W., Nellist M.D., Jansen F.E., Spliet W.G.M., Krsek P., Benova B., Zamecnik J., Crino P.B., Prayer D., Czech T., Wöhrer A., Rahimi J., Höftberger R., Hainfeller J.A., Feucht M., Aronica E.

PLOS One. 2016 Jun 13;11(6):e0157396. doi: 10.1371/journal.pone.0157396. eCollection 2016.


Tuberous Sclerosis Complex (TSC) is a genetic hamartoma syndrome frequently associated with severe intractable epilepsy. In some TSC patients epilepsy surgery is a promising treatment option provided that the epileptogenic zone can be precisely delineated. TSC brain lesions (cortical tubers) contain dysmorphic neurons, brightly eosinophilic giant cells and white matter alterations in various proportions. However, a histological classification system has not been established for tubers. Therefore, the aim of this study was to define distinct histological patterns within tubers based on semi-automated histological quantification and to find clinically significant correlations. In total, we studied 28 cortical tubers and seven samples of perituberal cortex from 28 TSC patients who had undergone epilepsy surgery. We assessed mammalian target of rapamycin complex 1 (mTORC1) activation, the number of giant cells, dysmorphic neurons, neurons, and oligodendrocytes, and calcification, gliosis, angiogenesis, inflammation and myelin content. Three distinct histological profiles emerged based on the proportion of calcifications, dysmorphic neurons and giant cells designated types A, B, and C. In the latter two types we were able to subsequently associate them with specific features on presurgical MRI. Therefore, these histopathological patterns provide consistent criteria for improved definition of the clinico-pathological features of cortical tubers identified by MRI and provide a basis for further exploration of the functional and molecular features of cortical tubers in TSC.