Neurological manifestations of tuberous sclerosis in children (own observations)

Tuberous sclerosis (Pringle-Burneville disease) is a polysystemic genetic disease and occurs in the population with a frequency of 1:50000. Objective of the study. To study neuropsychic status and dynamics of tuberous sclerosis development in children. Material and Methods. Have been examined 33 children aged from 1 to 14 years, who were observed in the neurological pediatric department of the University Clinic ("Aksay") of Asfendiyarov KazNMU. All children had apigmented spots and coffee-milk stains on the torso and extremities, not protruding above the skin level. All children showed characteristic neuroimaging changes in the brain by magnetic resonance imaging (MRI) and computed tomography (CT) - areas of dyshinesia cortically and subcortically, i.e. tubercles. As well as changes in internal organs (hamartoma variants). All children underwent a complete laboratory examination (general blood count, standard biochemical parameters), electroencephalography of the brain (EEG), as well as ultrasound examination of internal organs. Results and conclusions. As a result of our study, it was revealed that the main symptom confirming the diagnosis of tuberous sclerosis is the presence of tubers (95-100% of patients). Moreover, there is a topographical relationship between tubers detected during MRI examination and the presence of foci on the EEG. Thus, a particular manifestation of the disease in patients is symptomatic epilepsy with onset in the first months of life (96% of patients). Keywords: tuberous sclerosis, epilepsy, children, hamartomas, pigmented spots, cortical dysgenesis, tubers.

Intraventricular IL-17A administration activates microglia and alters their localization in the mouse embryo cerebral cortex

Viral infection during pregnancy has been suggested to increase the probability of autism spectrum disorder (ASD) in offspring via the phenomenon of maternal immune activation (MIA). This has been modeled in rodents. Maternal T helper 17 cells and the effector cytokine, interleukin 17A (IL-17A), play a central role in MIA-induced behavioral abnormalities and cortical dysgenesis, termed cortical patch. However, it is unclear how IL-17A acts on fetal brain cells to cause ASD pathologies. To assess the effect of IL-17A on cortical development, we directly administered IL-17A into the lateral ventricles of the fetal mouse brain. We analyzed injected brains focusing on microglia, which express IL-17A receptors. We found that IL-17A activated microglia and altered their localization in the cerebral cortex. Our data indicate that IL-17A activates cortical microglia, which leads to a cascade of ASD-related brain pathologies, including excessive phagocytosis of neural progenitor cells in the ventricular zone.

Intraventricular IL-17A Administration Activates Microglia and Alters Their Localization in the Mouse Embryo Cerebral Cortex

Viral infection during pregnancy has been suggested to increase the probability of autism spectrum disorder (ASD) in offspring via the phenomenon of maternal immune activation (MIA). This has been modeled in rodents. Maternal T helper 17 cells and the effector cytokine, interleukin 17A (IL-17A), play a central role in MIA-induced behavioral abnormalities and cortical dysgenesis, termed cortical patch. However, it is unclear how IL-17A acts on fetal brain cells to cause ASD pathologies. To assess the effect of IL-17A on cortical development, we directly administered IL-17A into the lateral ventricles of the fetal mouse brain. We analyzed injected brains focusing on microglia, which express IL-17A receptors. We found that IL-17A activated microglia and altered their localization in the cerebral cortex. Our data indicate that IL-17A activates cortical microglia, which leads to a cascade of ASD-related brain pathologies, including excessive phagocytosis of neural progenitor cells in the ventricular zone.

A de novo missense mutation in TUBA1A results in reduced neural progenitor survival and differentiation

ABSTRACTMutations in tubulins have been implicated in numerous human neurobiological disorders collectively known as “tubulinopathies.” We identified a patient with severe cortical dysgenesis and a novel de novo heterozygous missense mutation in Tubulin Alpha 1a (TUBA1A, c.1225 G>T). Induced pluripotent stem cells derived from this individual were differentiated into two dimensional neural rosette clusters to identify underlying mechanisms for the severe cortical dysgenesis phenotype. Patient-derived clones showed evidence of impaired neural progenitor survival and differentiation with abnormal neural rosette formation, increases in cell death, and fewer post-mitotic neurons. These features correlate with the drastically underdeveloped cortical tissues seen in the proband. This is the first experimental evidence in human tissue suggesting a mechanism underlying the role for TUBA1A in cortical development.SUMMARY STATEMENTVariants in tubulin genes often lead to severe congenital brain malformations. Here we identify a new mutation in TUBA1A and use iPSCS to show this alters proliferation, differentiation and survival of neural progenitors.