1,721,078 research outputs found
Erratum: Autism spectrum disorders in tuberous sclerosis: Pathogenetic pathways and implications for treatment (Journal of Child Neurology (2010) 25:7 (873-880) DOI: 10.1177/0883073810361789)
No full textAutism spectrum disorders in tuberous sclerosis: pathogenetic pathways and implications for treatment.
No full textAutism spectrum disorders have been reported as being much more frequent in individuals with tuberous sclerosis than in the general population. Previous studies have implicated early seizure onset and the localization of cortical tubers in the temporal lobes as risk factors for autism. However, the underlying reasons for this association remain largely unclear. The dysregulation of intracellular signaling through the activation of mTOR pathway could play a direct role in determining susceptibility to autism. Early control of seizures and an early intensive behavioral intervention of autism during the period of brain plasticity can mitigate, but not reverse the final outcome. A greater understanding of the pathogenetic mechanisms underlying autism in tuberous sclerosis could help in devising targeted and potentially more effective treatment strategies. © The Author(s) 2010
MTOR inhibitors as a new therapeutic option for epilepsy
No full textDysregulation of the mTOR signaling pathway is associated with highly epileptogenic conditions such as tuberous sclerosis, focal cortical dysplasia, hemimegalencephaly and ganglioglioma, grouped under the term of 'mTORopathies'. Brain abnormalities associated with mTOR overactivation include enlarged and dysplastic neurons, abnormal cortical organization and astrogliosis. mTOR signaling intervenes in several molecular/biochemical processes leading to epileptogenesis. Animal models demonstrated that mTOR inhibitors could exert both an anticonvulsant action and an antiepileptogenic effect in models of genetic and acquired epilepsy. Preliminary studies in patients affected by tuberous sclerosis and treated with rapamycin or everolimus demonstrated potential benefits in seizure frequency reduction, suggesting that mTOR inhibition could be a promising treatment option for mTORopathies-related epilepsy. The authors reviewed the current knowledge of mTOR overactivation in different forms of epilepsy, and discuss the potential clinical use of mTOR inhibitors
Autism in tuberous sclerosis: are risk factors identifiable and preventable?
No full text Evaluation of: Numis AL, Major P, Montenegro MA, Muzykevicz DA, Pulsifer MB, Thiele EA. Identification of risk factors for autism spectrum disorder in tuberous sclerosis complex. Neurology 76(11), 981–987 (2011). Autism spectrum disorders (ASDs) are much more frequent in individuals with tuberous sclerosis complex (TSC) than in the general population. However, the underlying reasons for this association remain largely unclear. This study aimed to identify some risk factors leading to autism in children with TSC. The authors analyzed epidemiological, genetic, electrophysiological and neuroanatomical risk factors in a cohort of 103 TSC patients. ASDs were diagnosed in 41 of the TSC patients (40%). Individuals with ASD had earlier age at seizure onset and a lower IQ (p < 0.001). There was a trend for patients with ASD to have the largest tuber burden in the left temporal lobe and mutations inactivating the hamartin domain of the TSC2 gene. They concluded that autism in TSC may be associated with early and persistent seizure activity in specific brain regions, particularly in the left temporal lobe, where areas responsible for social communication are localized. Cyst-like tubers were more common in TSC patients with ASD. </jats:p
Safety and tolerability profile of new antiepileptic drug treatment in children with epilepsy
No full textIntroduction: Treatment of pediatric epilepsy requires a careful evaluation of the safety and tolerability profile of antiepileptic drugs (AEDs) to avoid or minimize as much as possible adverse events (AEs) on various organs, hematological parameters, and growth, pubertal, motor, cognitive and behavioral development.Areas covered: Treatment-emergent AEs (TEAEs) reported in the literature 2000-2018 regarding second- and third-generation AEDs used in the pediatric age, with exclusion of the neonatal period that exhibits specific peculiarities, have been described on the basis of their frequency, severity/tolerability, and particular association with a given AED.Expert opinion: Somnolence/sedation and behavioral changes, like irritability and nervousness, are among the most commonly observed TEAEs associated with almost all AEDs. Lamotrigine, Gabapentin, Oxcarbazepine, and Levetiracetam appear to be the best-tolerated AEDs with a <= 2% withdrawal rate, while Tiagabine and Everolimus are discontinued in up to >20% of the patients because of intolerable TEAEs. For some AEDs, literature data are scanty to draw a high-level evidence on their safety and tolerability profile. The reasons are: insufficient population size, short duration of treatments, or lack of controlled trials. A future goal is that of identifying clearer, easier, and more homogeneous methodological strategies to facilitate AED testing in pediatric populations
Recent advances in neurobiology of Tuberous Sclerosis Complex
No full textTuberous Sclerosis Complex (TSC) is a multisystem genetic disorder with variable phenotypic expression, due to a muta- tion in one of the two genes, TSC1 and TSC2, and a subsequent hyperactivation of the downstream mTOR pathway, result- ing in increased cell growth and proliferation. The central nervous system is consistently involved in TSC, with 90% of individuals affected showing structural abnormalities, and almost all having some degree of CNS clinical manifestations, including seizures, cognitive impairment and behavioural problems. TSC is proving to be a particularly informative model for studying contemporary issues in developmental neurosciences. Recent advances in the neurobiology of TSC from molec- ular biology, molecular genetics, and animal model studies provide a better understanding of the pathogenesis of TSC-related neurological symptoms. Rapamycin normalizes the dysregulated mTOR pathway, and recent clinical trials have demonstrated its efficacy in various TSC manifestations, suggesting the possibility that rapamycin may have benefit in the treatment of TSC brain disease
Mammalian Target of Rapamycin Inhibitors and Life-Threatening Conditions in Tuberous Sclerosis Complex.
No full textTuberous sclerosis complex (TSC) is a multisystem disease associated with an overall reduction in life expectancy due to the possible occurrence of different life-threatening conditions. Subjects affected by TSC are, in fact, at risk of hydrocephalus secondary to the growth of subependymal giant cell astrocytomas, or of sudden unexpected death in epilepsy. Other nonneurological life-threatening conditions include abdominal bleeding owing to renal angiomyolipomas rupture, renal insufficiency due to progressive parenchymal destruction by multiple cysts, pulmonary complications due to lymphangioleiomyomatosis, and cardiac failure or arrhythmias secondary to rhabdomyomas. In the last decades, there has been a great progress in understanding the pathophysiology of TSC-related manifestations, which are mainly linked to the hyperactivation of the so-called mammalian target of rapamycin (mTOR) pathway, as a consequence of the mutation in 1 of the 2 genes TSC1 or TSC2. This led to the development of new treatment strategies for this disease. In fact, it is now available as a biologically targeted therapy with everolimus, a selective mTOR inhibitor, which has been licensed in Europe and USA for the treatment of subependymal giant cell astrocytomas and angiomyolipomas in subjects with TSC. This drug also proved to benefit other TSC-related manifestations, including pulmonary lymphangioleiomyomatosis, cardiac rhabdomyomas, and presumably epileptic seizures. mTOR inhibitors are thus proving to be a systemic therapy able to simultaneously address different and potentially life-threatening complications, giving the hope of improving life expectation in individuals with TSC
Syndromic autism: Causes and pathogenetic pathways
No full textAutism is a severe neurodevelopmental disorder known to have many different etiologies. In the last few years, significant progresses have been made in comprehending the causes of autism and their multiple impacts on the developing brain. This article aims to review the current understanding of the etiologies and the multiple pathogenetic pathways that are likely to lead to the autistic phenotype
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