authors: D'Gama AM., Geng Y., Couto JA., Martin B., Boyle EA., LaCoursiere CM., Hossain A., Hatem NE., Barry BJ., Kwiatkowski DJ., Vinters HV., Barkovich AJ., Shendure J., Mathern GW., Walsh GA., Poduri A.

Ann Neurol. 2015 Apr;77(4):720-5. doi: 10.1002/ana.24357.


Focalmalformations of cortical development, including focalcortical dysplasia (FCD) and hemimegalencephaly (HME), are important causes of intractable childhood epilepsy. Using targeted and exome sequencing on DNA from resected brain samples and nonbrain samples from 53 patients with FCD or HME, we identified pathogenic germline and mosaic mutations in multiple PI3K/AKT pathway genes in 9 patients, and a likely pathogenic variant in 1 additional patient. Our data confirm the association of DEPDC5 with sporadic FCD but also implicate this gene for the first time in HME. Our findings suggest that modulation of the mammalian target of rapamycinpathway may hold promise for malformation-associated epilepsy.

authors: Leech JD., Lammers SH., Goldman S., Auricchio N., Bronson RT., Kwiatkowski D., Sahin M. 

Mol Cancer Res. 2015 Mar;13(3):548-55. doi: 10.1158/1541-7786.MCR-14-0178


Tuberous sclerosis complex (TSC) is an autosomal disease caused by inactivating mutations in either of the tumorsuppressor genes TSC1 or TSC2. TSC-associated tumor growth is present in multiple tissues and organs including brain, kidney, liver, heart, lungs, and skin. In the kidney, TSC angiomyolipomas have aberrant vascular structures with abnormal endothelial cells, suggesting a role for endothelial mTORC1 function. In the current report, a genetically engineered mousemodel (GEMM) with a conditional knockout allele of Tsc1 with a Darpp32-Cre allele displayed accelerated formation of both kidney cystadenomas and paw hemangiosarcomas. All mutant mice developed hemangiosarcomas on multiple paws by 6 weeks of age. By 16 weeks of age, the average mutant hind paw was 4.0 mm in diameter, nearly double the size of control mice. Furthermore, the hemangiosarcomas and kidney cystadenomas were responsive to intraperitoneal rapamycin treatment. Immunoblotting and immunostaining for phospho-S6 (pS6) and phospho-CAD showed that the effect of rapamycin on tumor size was through inhibition of the mTOR signaling pathway. Finally, elevated VEGF mRNA levels were also observed in hemangiosarcoma specimens. Because paw hemangiosarcomas are easily detectable and scorable for size and growth, this novel mouse model enables accelerated in vivo drug testing for therapies of TSC-related tumors.

Implications: These findings provide a strong rationale for simultaneous use of this conditional knockout mouse as an in vivo genetic model while seeking new cancer therapies for TSC-related tumors. 

authors: Blümcke I., Aronica E., Miyata H., Sarnat HB., Thom M., Roessler K., Rydenhag B., Jehi L., Krsek P., Wiebe S., Spreafico R. 

Epilepsia. 2016 Mar;57(3): 348-58. doi: 10.1111/epi.13319


Epilepsy surgery is an effective treatment in many patients with drug-resistant focal epilepsies. An early decision for surgical therapy is facilitated by a magnetic resonance imaging (MRI)-visible brain lesion congruent with the electrophysiologically abnormal brain region. Recent advances in the pathologic diagnosis and classification of epileptogenic brain lesions are helpful for clinical correlation, outcome stratification, and patient management. However, application of international consensus classification systems to common epileptic pathologies (e.g. focal cortical dysplasia (FCD) and hippocampal sclerosis (HS)) necessitates standardized protocols for neuropathologic workup op epilepsy surgery specimens. To this end, the Task Force of Neuropathology from the International League Against Epilepsy (ILAE) Commission on Diagnostic Methods developed a consensus standard operational procedure for tissue inspection, distribution and processing. The aims are to provide a systematic framework for histopathologic workup, meeting minimal standards and maximizing current and future opportunities for morphofunctional correlations and molecular studies for both clinical care and research. Whenever feasible, anatomically intact surgical specimens are desirable to enable systematic analysis in selective hippocampectomies, temporal lobe resections, and lesional or nonlesional neocortical samples. Correct orientation of sample and the sample's relation to neurophysiologically aberrant sites requires good communication between pathology and neurosurgical teams. Systematic tissue sampling of 5-mm slabs along a defined anatomic axis and application of a limited immunohistochemical panel will ensure a reliable differential diagnosis of main pathologies encountered in epilepsy surgery. 

authors: Curatolo P., Aronica E., Jansen A., Jansen F., Kotulska K., Lagae L., Moavero R., Jozwiak S.

Eur J Paediatr Neurol. 2016 Mar;20(2):203-11. doi: 10.1016/j.ejpn.2015.12.005.


Background: In tuberous sclerosis complex (TSC) a relationship has been shown between early and refractory seizures and intellectual disability. However, it is uncertain whether epilepsy in TSC is simply a marker in infants who are destined to develop an encephalopathic process or if seizures play a causal role in developing encephalopathy. 

Methods: This paper summarizes the key points discussed during a European TSC workshop held in Rome and reviews the experimental and clinical evidence in support of the two theories. 

Results/conclusion: There are many factors that influence the appearance of both early seizure onset and the encephalopathy resulting in neurodevelopmental deficits. Experimental studies show that as a consequence of the TSC genes mutation, mammalian target of Rapamycin (mTOR) overactivation determines an alteration in cellular morphology with cytomegalic neurons, altered synaptogenesis and an imbalance between excitation/inhibition, thus providing a likely neuroanatomical substrate for the early appearance of refractory seizures and for the encephalopathic process. At the clinical level, early signs of altered developmental trajectories are often unrecognized before 12 months of age. Evidence from experimental research shows that encephalopathy in TSC might have a genetic cause, and mTOR activation caused by TSC gene mutation can be directly responsible for the early appearance of seizures and encephalopathy.  

authors: Boison D., Aronica E.

Neuropharmacology. 2015 Oct;97:18-34. doi:10.1016/j.neuropharm.2015.04.031


Comorbidities in Neurology represent a major conceptual and therapeutic challenge. For example, temporal lobe epilepsy (TLE) is a syndrome comprised of epileptic seizures and comorbid symptoms including memory and psychiatric impairment, depression, and sleep dysfunction. Similarly, Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are accompanied by various degrees of memory dysfunction. Patients with AD have an increased likelihood for seizures, whereas all four conditions share certain aspects of psychosis, depression and sleep dysfunction. This remarkable overlap suggests common pathophysiological mechanisms, which include synaptic dysfunction and synaptotoxicity, as well as glial activation and astrogliosis. Astrogliosis is linked to synapse function via the tripartite synapse, but astrocytes also control the availability of gliotransmitters and adenosine. Here we will specifically focus on the adenosine hypothesis of comorbidities' implying that astrocyte activation, via overexpression of adenosine kinase (ADK), induces a deficiency in the homeostatic tone of adenosine. We present evidence from patient-derived samples showing astrogliosis and overexpression of ADK as common pathological hallmark of epilepsy, AD, PD and ALS. We discuss a transgenic 'comorbidity model', in which brain-wide overexpression of ADK and resulting adenosine deficiency produces a comorbid spectrum of seizures, altered dopaminergic function, attentional impairment, and deficits in cognitive domains and sleep regulation. We conclude that dysfunction of adenosine signaling is common in neurological conditions, that adenosine dysfunction can explain co-morbid phenotypes, and that therapeutic adenosine augmentation might be effective for the treatment of comorbid symptoms in multiple neurological conditions.