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Precision medicine in stroke and other related neurological diseases
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Anjana Munshi, Vandana Sharma, Sulena Singh
The understanding of mechanisms of neuronal alteration and maintenance of their molecular signatures during disease progression is a major requirement for clinically correct diagnosis of neurological disease. Numerous diagnostic investigations, including imaging techniques, are opted by concerned clinicians for prediction and analysis of the disease. Apart from these diagnostic measures, genomic profiling is one of the cornerstones of precision or personalized therapy, which not only forecasts the susceptibility to disease but also predicts the best possible treatment for the individual patient. Many genes, including ATP binding cassette subfamily A member 7 (ABCA7), bridging integrator 1 (BIN1), complement receptor 1 (CR1), phospholipase D3 gene (PLD3), and phosphatidylinositol-binding clathrin assembly protein gene (PICALM), have been revealed to contribute toward the excess burden of deleterious coding mutations in Alzheimer's disease (Ma et al., 2014; Jiang et al., 2014; Tan et al., 2014b; Cacace et al., 2015; Vardarajan et al., 2015). In the epileptic encephalopathies, trio exome sequencing has identified that genes UDP-N-acetylglucosaminyltransferase subunit (ALG), gamma-aminobutyric acid type a receptor β3 gene (GABRB3), dynamin 1 (DNM1), hyperpolarization activated cyclic nucleotide gated potassium channel 1 (HCN1), glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A), gamma-aminobutyric acid type A receptor alpha1 subunit (GABRA1), G protein subunit alpha O1 (GNAO1), potassium sodium-activated channel subfamily T member 1 (KCNT1), sodium voltage-gated channel alpha subunit 2 (SCN2A), sodium voltage-gated channel alpha subunit 8 (SCN8A), and solute carrier family 35 member A2 (SLC35A2) are associated with epileptogenesis. Many of the proteins encoded by these genes have been found to be associated with synaptic transmission (Epi, 2015).
Approaches for the discovery of drugs that target K Na 1.1 channels in KCNT1-associated epilepsy
Published in Expert Opinion on Drug Discovery, 2022
Barbara Miziak, Stanisław J Czuczwar
As already mentioned, the KCNT1 gene, is responsible for encoding sodium-activated potassium channels. Known mutations, altering the function of potassium channels, lead to the development of severe epilepsy and significant intellectual impairment [7,10,12]. The research data indicate that most of the disruption is localized to the extended cytoplasmic C-terminus of KNa 1.1 channels, resulting in increased potassium current [55]. One such example is the phosphorylation of this site by protein kinase C, which results in a rapid amplitude of potassium currents [10,55]. Studies indicate that this element is responsible for binding cytoplasmic signaling proteins, including Phactr1, which, by binding actin, recruits protein phosphatase 1 (PP1) to certain phosphoprotein substrates [55]. Other proteins have also been shown to be present, for example, FMRP, PSD95, CYFIP1, and TMEM16C, but their role is not yet as well understood [26,50,56]. Selected mutations on a KNa1.1 protein are presented in Figure 1.
The safety of treating newly diagnosed epilepsy
Published in Expert Opinion on Drug Safety, 2019
Compared to avoiding certain AEDs in genetically at-risk individuals to improve safety, success in using genetic information to improve treatment efficacy has been more limited. In theory, employing specific therapies to causative mutations can potentially minimize the burden of polytherapy and improve epilepsy severity [92]. Mutations in the KCNT1 gene responsible for a type of calcium-activated potassium channel, for example, are associated with the development of severe epilepsies including autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In-vitro studies [107] and case series [108] supported the potential use of quinidine, an anti-malarial agent, in KCNT1 epilepsies. However, a recent clinical trial of quinidine in six individuals with ADNFLE caused by KCNT1-mutation resulted in no significant reduction in seizure frequency, possibly because of the limitation of dosage by cardiotoxicity [109].
Personalized treatment in the epilepsies: challenges and opportunities
Published in Expert Review of Precision Medicine and Drug Development, 2018
Simona Balestrini, Sanjay M Sisodiya
The gene KCNT1 encodes a sodium-dependent potassium channel and is activated by increased intracellular chloride and sodium concentrations; it is responsible for the slow hyperpolarization of the transmembrane potential during action potentials [54]. KCNT1 gain-of-function mutations are reported to cause early onset epileptic encephalopathies including epilepsy of infancy with migrating focal seizures. In vitro testing has indicated that the electrophysiological defect of at least some of these mutations may be reversed by quinidine, an antiarrhythmic drug, which is a partial blocker of KCNT1[55]. In three cases of epilepsy of infancy with migrating seizures due to KCNT1 mutations, quinidine resulted in decreased seizure frequency or freedom from seizures and improved psychomotor development [56–58]. However, another two cases with early onset epileptic encephalopathy associated with KCNT1 mutations manifesting gain-of-function in vitro, one showing a novel phenotype with developmental regression and severe nocturnal focal and secondarily generalized seizures starting in early childhood and the other with early onset epileptic encephalopathy [57,59] did not respond to treatment with quinidine. The current evidence suggests that quinidine represents a promising candidate for a precision medicine approach in some KNCT1-related epilepsy syndromes, but further studies in larger cohorts of patients are necessary to clarify its effectiveness.