Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Astrocytes are an attractive cell target for gene therapy, but the validation of new therapeutic candidates is needed. We determined whether adeno-associated viral (AAV) vector-mediated overexpression of glutamine synthetase (GS) or excitatory amino-acid transporter 2 (EAAT2), or expression of microRNA targeting adenosine kinase (miR-ADK) in hippocampal astrocytes in the rat brain could modulate susceptibility to kainate-induced seizures and neuronal cell loss. Transgene expression was found predominantly in astrocytes following direct injection of glial-targeting AAV9 vectors by 3 weeks postinjection. ADK expression in miR-ADK vector-injected rats was reduced by 94-96% and was associated with an ~50% reduction in the duration of kainate-induced seizures and greater protection of dentate hilar neurons but not CA3 neurons compared with miR-control vector-injected rats. In contrast, infusion of AAV-GS and EAAT2 vectors did not afford any protection against seizures or neuronal damage as the level of transcriptional activity of the glial fibrillary acidic promoter was too low to drive any significant increase in transgenic GS or EAAT2 relative to the high endogenous levels of these proteins. Our findings support ADK as a prime therapeutic target for gene therapy of temporal lobe epilepsy and suggest that alternative approaches including the use of stronger glial promoters are needed to increase transgenic GS and EAAT2 expression to levels that may be required to affect seizure induction and propagation.
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PMID:Adenosine kinase, glutamine synthetase and EAAT2 as gene therapy targets for temporal lobe epilepsy. 2523 Nov 74

Intellectual disabilities (ID) are etiologically heterogeneous. Advanced molecular techniques could be helpful in identification of the underlying genetic defects. We aimed to characterize clinical and molecular features of three Thai patients with ID. Patient 1 had ID, hypotonia and lactic acidosis. Patient 2 had ID and growth failure. Patient 3 had ID, seizure, diarrhea and hypoglycemia. Whole exome sequencing found that Patient 1 was homozygous for a nonsense, c.1303C>T (p.Arg435Ter), mutation in FBXL4, a gene responsible for encephalomyopathic mitochondrial DNA depletion syndrome-13 (MTDPS13). Patient 2 was compound heterozygous for two novel mutations, c.3226C>T (p.Arg1076Ter) and c.3205C>T (p.Arg1069Ter), in UNC80, a known gene of infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2). Patient 3 was homozygous for a novel missense, c.427T>C (p.Cys143Arg), mutation in ADK, a known gene of adenosine kinase deficiency leading to hypermethioninemia. This study expands the mutational spectra of ID genes.
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PMID:Whole exome sequencing revealed mutations in FBXL4, UNC80, and ADK in Thai patients with severe intellectual disabilities. 3077 78

Epilepsy, an ancient disease, is defined as an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition. Antiepileptic drugs (AEDs) are currently used as first-line treatment for patients with epilepsy; however, around 36% of patients are diagnosed with refractory epilepsy, which means two or more AEDs have been considered as failed after sufficiently correct usage. Unfortunately, it is unlikely that the improvement of the efficacy of AEDs will be easily achieved, especially since no AEDs show efficacy in ceasing epileptogenesis. Consequently, several endogenous anticonvulsants attract investigators and epileptologists, such as galanin, cannabis, and adenosine. Astrogliosis is a neuropathological hallmark of epilepsy, whatever the etiology is, and astrogliosis is frequently associated with overexpression of adenosine kinase, which means downregulation of synaptic levels of adenosine. Consequently, adenosine is negatively regulated by adenosine kinase through the astrocyte-based cycle. On the other hand, focal adenosine augmentation therapy, using adenosine kinase inhibitor, has been proved to be effective for reducing seizures in both animal models and in vitro human brain tissue resected from a variety of etiology of refractory epilepsy patients. In addition to reducing seizures, adenosine augmentation therapy can also palliate co-morbidities, like sleep, cognition, or depression. Of importance, transgenic mice with reduced ADK were resistant to epileptogenesis induced by acute brain injury. In terms of translation, based on findings of adenosinerelated epileptogenic mechanisms, the application into clinical practice seems to be feasible by molecular strategies that have been already experimentally implemented, including gene and RNA interference. In the present review, we will focus on the evidence of ADK dysfunction in the epileptic brain from human beings and animals, and review the role of ADK inhibitor in adenosine augmentation therapy and the underlying mechanism of prevention of epileptogenesis.
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PMID:Role of Adenosine Kinase Inhibitor in Adenosine Augmentation Therapy for Epilepsy: A Potential Novel Drug for Epilepsy. 3163 74