It is just over a decade since the discovery of the first human epilepsy associated ion channel gene mutation. Since then mutations in at least 25 different genes have been described, although the strength of the evidence for these genes having a pathogenic role in epilepsy varies. These discoveries are allowing us to gradually begin to unravel the molecular basis of this complex disease. In the epilepsies, virtually all the established genes code for ion channel subunits. This has led to the concept that the idiopathic epilepsies are a family of channelopathies. This review first introduces the epilepsy syndromes linked to mutations in the various genes. Next it collates the genetic and functional analysis of these genes. This part of the review is divided into voltage-gated channels (Na+, K+, Ca2+, Cl(-) and HCN), ligand-gated channels (nicotinic acetylcholine and GABA(A) receptors) and miscellaneous proteins. In some cases significant advances have been made in our understanding of the molecular and cellular deficits caused by mutations. However, the link between molecular deficit and clinical phenotype is still unknown. Piecing together this puzzle should allow us to understand the underlying pathology of epilepsy ultimately providing novel therapeutic strategies to complete the clinic-bench-clinic cycle.
"Family studies reveal that the overall recurrence risk for epilepsy in first-degree relatives of affected individuals is 2–5 % [4, 5], and at least one study has shown that there is similar increased recurrence for family members of probands with either generalized or focal epilepsy . Finally, large multiplex families in which epilepsy segregates in an autosomal dominant manner have been used to identify linkage regions and causative genes in several different epilepsy syndromes . "
[Show abstract][Hide abstract] ABSTRACT: Copy number variants (CNVs) are deletions or duplications of DNA. CNVs have been increasingly recognized as an important source of both normal genetic variation and pathogenic mutation. Technologies for genome-wide discovery of CNVs facilitate studies of large cohorts of patients and controls to identify CNVs that cause increased risk for disease. Over the past 5 years, studies of patients with epilepsy confirm that both recurrent and non-recurrent CNVs are an important source of mutation for patients with various forms of epilepsy. Here, we will review the latest findings and explore the clinical implications.
"The most frequent causes of epileptic seizures in infants are genetic factors, perinatal hypoxia/asfixia, intracranial trauma, congenital malformations of the brain, or infections   . In young children and adolescents, epilepsy is usually related to genetic factors , whereas in adults, the etiology can be attributed more to cerebrovascular diseases, head injury and brain tumors  . "
[Show abstract][Hide abstract] ABSTRACT: In a previous study, we uncovered the anticonvulsant properties of turmeric oil and its sesquiterpenoids (ar-turmerone, α-, β-turmerone and α-atlantone) in both zebrafish and mouse models of chemically-induced seizures using pentylenetetrazole (PTZ). In this follow-up study, we aimed at evaluating the anticonvulsant activity of ar-turmerone further. A more in-depth anticonvulsant evaluation of ar-turmerone was therefore carried out in the i.v. PTZ and 6-Hz mouse models. The potential toxic effects of ar-turmerone were evaluated using the beam walking test to assess mouse motor function and balance. In addition, determination of the concentration-time profile of ar-turmerone was carried out for a more extended evaluation of its bioavailability in the mouse brain. Ar-turmerone displayed anticonvulsant properties in both acute seizure models in mice and modulated the expression patterns of two seizure-related genes (c-fos and brain-derived neurotrophic factor [bdnf]) in zebrafish. Importantly, no effects on motor function and balance were observed in mice after treatment with ar-turmerone even after administering a dose 500-fold higher than the effective dose in the 6-Hz model. In addition, quantification of its concentration in mouse brains revealed rapid absorption after i.p. administration, capacity to cross the BBB and long-term brain residence. Hence, our results provide additional information on the anticonvulsant properties of ar-turmerone and support further evaluation towards elucidating its mechanism of action, bioavailability, toxicity and potential clinical application.
PLoS ONE 12/2013; 8(12):e81634. DOI:10.1371/journal.pone.0081634 · 3.23 Impact Factor
"It is hypothesized that dysfunctional Na + , K + , Cl − , or Ca 2+ channels alter the threshold for neuronal depolarization and action potential firing, thereby shifting the balance between excitation and inhibition. At the microscopic level, epileptic brain regions are characterized by injured neurons, gliosis, axonal sprouting, and the formation of new, aberrant, synaptic connections (reviewed in D'Ambrosio, 2004; Dichter, 2009; Reid et al., 2009). Cx43 is abundant in astrocytes and can additionally be found in activated microglia, developing neurons, and endothelial cells (Orellana et al., 2009, 2011; Avila et al., 2011; Wang et al., 2012b) (Figure 1). "
[Show abstract][Hide abstract] ABSTRACT: The coordination of tissue function is mediated by gap junctions (GJs) that enable direct cell-cell transfer of metabolic and electric signals. GJs are formed by connexins of which Cx43 is most widespread in the human body. In the brain, Cx43 GJs are mostly found in astroglia where they coordinate the propagation of Ca(2+) waves, spatial K(+) buffering, and distribution of glucose. Beyond its role in direct intercellular communication, Cx43 also forms unapposed, non-junctional hemichannels in the plasma membrane of glial cells. These allow the passage of several neuro- and gliotransmitters that may, combined with downstream paracrine signaling, complement direct GJ communication among glial cells and sustain glial-neuronal signaling. Mutations in the GJA1 gene encoding Cx43 have been identified in a rare, mostly autosomal dominant syndrome called oculodentodigital dysplasia (ODDD). ODDD patients display a pleiotropic phenotype reflected by eye, hand, teeth, and foot abnormalities, as well as craniofacial and bone malformations. Remarkably, neurological symptoms such as dysarthria, neurogenic bladder (manifested as urinary incontinence), spasticity or muscle weakness, ataxia, and epilepsy are other prominent features observed in ODDD patients. Over 10 mutations detected in patients diagnosed with neurological disorders are associated with altered functionality of Cx43 GJs/hemichannels, but the link between ODDD-related abnormal channel activities and neurologic phenotype is still elusive. Here, we present an overview on the nature of the mutants conveying structural and functional changes of Cx43 channels and discuss available evidence for aberrant Cx43 GJ and hemichannel function. In a final step, we examine the possibilities of how channel dysfunction may lead to some of the neurological manifestations of ODDD.
Frontiers in Pharmacology 09/2013; 4:120. DOI:10.3389/fphar.2013.00120 · 3.80 Impact Factor
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