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Ion Channels in Human Pluripotent Stem Cells and Their Neural Derivatives
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Ritika Raghavan, Robert Juniewicz, Maharaib Syed, Michael Lin, Peng Jiang
Human iPSCs and ESCs are morphologically identical and largely share electrophysiological properties at the pluripotent state. They appear to both be electrophysiologically homogenous, with both cell types exhibiting depolarization-activated delayed rectifier K+ currents (IKDR) and 4-aminopyradine (4-AP) sensitive currents but not voltage-gated sodium channel currents (INa), voltage-gated calcium currents (ICa)and Ca2+ activated K+ currents (IKCa) (33). At transcriptomic level, the expression of transcripts encoding ion channels could not be distinguished in hESCs and hiPSCs. KCNQ2 transcript has the highest expression in both hiPSCs and hESCs, which encodes the non-inactivating, slowly deactivating M-current (33,34). Also expressed in both hiPSC and hESCs are CNC4, which encodes delayed rectifier voltage-gated potassium channels (Kv3.4), and KCNS3 which encodes the silent modulatory α-subunit of IKDR channels (33). The detection of IKDR was at a high current density (47.5 ± 7.9 pA/pF at +40 mV) for both hESCs and hiPSCs and these IKDR are believed to have a role in proliferation (33,34). Tetraethylammonium (TEA), a blocker of IKDR, dose-dependently inhibited hESC proliferation with an EC50 of 11.6 ± 2.0mM and hiPSC proliferation with an EC50 of 7.8 ± 1.2 mM (33,34).
Cerebral palsy, cerebellar ataxia, AIDS, phacomatosis, neuromuscular disorders, and epilepsy
Published in Jacques Corcos, David Ginsberg, Gilles Karsenty, Textbook of the Neurogenic Bladder, 2015
Christopher Kobylecki, Ling K. Lee, Mark W. Kellett
The novel antiepileptic drug retigabine, an activator of KCNQ2/3 potassium channels, has been shown to cause urinary hesitancy and retention in a number of patients, leading to recommendations for its use with caution in patients at risk of urinary retention.189,190 This adverse effect seems consistent with the documented pharmacological effects of retigabine on smooth muscle in preclinical studies.191
Neurogenetics
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
Sonia Gandhi, Sarah Tabrizi, Nicholas Wood
There are relatively few single gene disorders that result in inherited forms of epilepsy, and these are usually caused by mutations in ion channels or neurotransmitter genes. For example, severe myoclonic epilepsy of infancy is caused by mutations in the a1 subunit of the sodium channel gene SCN1A. Mutations in the b1 subunit of the sodium channel gene SCN1B may cause generalized epilepsy with febrile seizures-plus (GEFS +). Benign infantile neonatal epilepsy is caused by mutations in the potassium channel genes, KCNQ2 or KCNQ3. Juvenile myoclonic epilepsy has been associated with mutations in the chloride channel gene CLCN2.
Genetic and clinical variations of developmental epileptic encephalopathies
Published in Neurological Research, 2023
Gül Demet Kaya Özçora, Elif Söbü, Uğur Gümüş
Developmental and epileptic encephalopathy type 7 (DEE 7) was the most common type in our study group. DEE 7 is frequently characterised by neonatal-onset refractory seizures, delayed neurodevelopment and persistent neurologic deficits. Seizures resolve by 3–4 years of age with improvement in EEG abnormalities. The severity of the disease may vary within the family. In our study, all patients with DEE 7 had neonatal seizures. The initial EEGs of patients 6 and 9 revealed a burst-suppression pattern that could subsequently progress to multifocal epileptiform activity (MFED), and were consistent with a clinical diagnosis of Ohtahara syndrome. Patients 6 and 9 were exitus, patient 7 was followed because of refractory epilepsy and patient 8 was developing close to normal. Dysmorphology was also present in patients 6 and 9. The authors note that the phenotypic variability could be due to the interplay of pathogenic mutations, modifying genes and more subtle environmental factors. In children with self-limiting neonatal epilepsy due to a pathogenic KCNQ2 variant, the flow of brain potassium ions is disturbed but to a lesser extent than in children with KCNQ2 developmental and epileptic encephalopathy. This difference possibly explains why these children have less severe disease than children with KCNQ2 developmental and epileptic encephalopathy [19–22]. In our study, the form with the most severe phenotype and the most resistant seizures was seen in DEE 7 and half of these patients died. Patients 6, 7 and 9 had de-novo mutations and patient 8 had a familial mutation and mild phenotypic features.
Learnings in developmental and epileptic encephalopathies: what do we know?
Published in Expert Review of Neurotherapeutics, 2023
Martina Giorgia Perinelli, Antonella Riva, Elisabetta Amadori, Roberta Follo, Pasquale Striano
It is well recognized that KCNQ2 encephalopathy is characterized by neonatal onset and cognitive lowering followed by seizure onset within the first few days of life [26]. However, different phenotypes can result from KCNQ2 pathogenic variants, from self-limited neonatal epilepsy to Ohtahara syndrome and infantile spasms [27,28]. Neuroimaging studies [26] revealed signal abnormalities in the basal ganglia or thalamus during the neonatal period. Dystonia, spasticity, hypotonia, cortical visual impairment, abnormal eye movements, and feeding intolerance can occur [26–28]. Further, patients may have severe motor impairments [29]. Notwithstanding, most children present learning difficulties even after seizures have ceased [27] that may be the result of the profound cognitive decline, the cortical visual and motor impairments. However, to date, no specific studies examining learning skills with standardized testing have been conducted.
Potassium channels as prominent targets and tools for the treatment of epilepsy
Published in Expert Opinion on Therapeutic Targets, 2021
Out of a wide spectrum of potassium channels, voltage-gated potassium channels are the main focus in epilepsy research (Table 1). Mutations of genes encoding pore-forming or accessory subunits of the channels have been found in humans with epilepsy, mostly in relatively uncommon autosomal dominant epilepsies. Mutations of Kv7.2/7.3 channels are accepted to be linked with several forms of epilepsy, mainly with those with neonatal onset [50]. Multiple mutations of Kv7.2 channel have been associated with various epileptic phenotypes, ranging from the mild epileptic syndrome (benign familial neonatal epilepsy, BFNE) to early onset severe epileptic encephalopathy with pharmacoresistant seizures and neurological impairment (KCNQ2/Kv7.2 encephalopathy) [51–56]. A linkage between the phenotype of KCNQ2-associated epilepsy and gene location of pathogenic missense variants of KCNQ2 subunit [57] as well as the mutation-induced functional impairments [53,58] have been reported. Kv7.3 channel mutations were also identified in BFNE and benign familial infantile epilepsy with developmental delay and intellectual disability [59,60]. The degree of the functional impairment caused by mutations at position 330 in KCNQ3 is suggested to contribute to clinical disease severity [61].