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Hyperkinetic Movement Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Morales-Briceno Hugo, Victor S.C. Fung, Annu Aggarwal, Philip Thompson
Epileptic encephalopathies associated with chorea:28GNAO1 mutations.SCN1A-related phenotypic.FOXG1 mutations.SCN8A mutations.SCN2A-related disorders.UBA5 mutations.DNM1 mutations.FRRS1L mutations.GRIN1/GRIN2B/GRIN2D mutations.
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).
Thalamic neuromodulation in epilepsy: A primer for emerging circuit-based therapies
Published in Expert Review of Neurotherapeutics, 2023
Bryan Zheng, David D. Liu, Brian B Theyel, Hael Abdulrazeq, Anna R. Kimata, Peter M Lauro, Wael F. Asaad
TRN circuits have been studied extensively in animal models of generalized seizure pathogenesis. Without the GABAergic reticular nucleus, unconstrained excitatory activity in these loops would freely amplify, and so manipulation of TRN responses may be clinically relevant[143]. Because indirect cortico-thalamic inhibition via the TRN usually outweighs direct corticothalamic excitation, loss of normal neocortical activation of the TRN can result in downstream disinhibition of the dorsal thalamus[87]. Consistent with this, experimental models of generalized-absence epilepsy in mice revealed pathologic synchrony via corticothalamic transmission when normal TRN recruitment was weakened by altered ion channels (Gria4)[144]. Similarly, knockout of Scn8a sodium channels in TRN neurons caused seizures by impairing tonic firing and recurrent desynchronization mechanisms[145,146]. These observations suggest restoring or amplifying TRN-mediated inhibitory mechanisms could promote seizure control[147–149].
Association of sodium voltage-gated channel genes polymorphisms with epilepsy risk and prognosis in the Saudi population
Published in Annals of Medicine, 2022
Mansour A. Alghamdi, Laith N. AL-Eitan, Ashwag Asiri, Doaa M. Rababa’h, Sultan A. Alqahtani, Mohammed S. Aldarami, Manar A. Alsaeedi, Raghad S. Almuidh, Abdulbari A. Alzahrani, Ahmad H. Sakah, Eman Mohamad El Nashar, Mansour Y. Otaif, Nawal F. Abdel Ghaffar
The available data that describe the association between SCN3A variants and epilepsy are limited and few were correlated to focal epilepsy [19]. rs1057518801 and rs1057520753 of SCN3A manifest a gain of function in sodium channels that results in more hyperpolarized potentials and had been linked to early infantile epileptic encephalopathy [20]. SCN1B and SCN2B gene have been associated with GEFS [21,22] and dravet syndrome [13,23]. rs786205830 is a loss of function mutation in the SCN1B gene had been linked to early infantile developmental and epileptic encephalopathy (Aeby et al. 2019). SCN8A has been reported to influence epilepsy at four months of early life and can affect the development. This gene may also enhance several epilepsy syndromes such as Lennox-Gastaut syndrome, West syndrome and epileptic encephalopathies (e.g. Dravet syndrome) [16]. Moreover, SCN8A also related to EIEE and BFIS (Makoff et al. 2009).
Current and future pharmacotherapy options for drug-resistant epilepsy
Published in Expert Opinion on Pharmacotherapy, 2022
NBI-921352 (XEN 901) is a sulfonamide and selective inhibitor of Nav 1.6 sodium channels. The gene SCN8A encodes the Nav 1.6 channel. Gain-of-function mutations in the SCN8A gene can result in severe childhood encephalopathies including Early Infantile Epileptic Encephalopathy (EIEE13), SCN8A developmental and epileptic encephalopathies [78]. Selective inhibition of Nav 1.6 could therefore target the underlying etiological pathways in these epileptic encephalopathies. There is extensive preclinical evidence that NBI-921352 is protective against induced seizures tested in the Maximal Electroshock Seizure (MES) test in mice and rats, as well as transgenic mice that have a gain-of-function mutation of SCN8A [79]. At present, two phase I studies have been conducted using NBI-921352 in healthy subjects [70] finding that NBI-921352 was well tolerated with no clinically significant trends in vital signs in the study cohorts. Phase II studies utilizing NBI-921352 for SCN8A developmental and epileptic encephalopathies as well as adult focal epilepsy are currently recruiting (NCT05226780, NCT04873869, NCT05159908).