Mechanisms of human inherited epilepsies. Prog Neurobiol.

Howard Florey Institute, The University of Melbourne, Parkville, Melbourne, Australia.
Progress in Neurobiology (Impact Factor: 10.3). 11/2008; 87(1):41-57. DOI: 10.1016/j.pneurobio.2008.09.016
Source: PubMed

ABSTRACT 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.

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    • "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). "
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    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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    • "There are several reports of seizures triggered with lack of food or after prolonged exercise [2] [3]. Seizures are also very common in patients with impaired transport of glucose across the blood–brain barrier due to deficiency of the major brain glucose transporter GLUT1 [4] [5] [6]. These seizures can occur not only in the classical severe GLUT1 encephalopathy but also in milder cases that have otherwise typical idiopathic generalized epilepsy [5] [6]. "
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    ABSTRACT: OBJECTIVE: We used transcranial magnetic stimulation (TMS) to investigate motor cortical excitability changes in relation to blood glucose levels. METHODS: Twenty-two drug-naïve patients with epilepsy [11 generalized and 11 focal] and 10 controls were studied twice on the same day; first after 12h of fasting and then 2h postprandial. Motor threshold and paired-pulse TMS at a number of short and long interstimulus intervals were measured. Serum glucose levels were measured each time. RESULTS: Decreased long intracortical inhibition was seen in patients and controls during fasting compared to postprandial studies. This effect was much more prominent in patients with generalized epilepsy (with effect sizes of up to 0.8) in whom there was also evidence of increased intracortical facilitation (effect size: 0.3). CONCLUSION: Cortical excitability varies with fluctuations in blood glucose levels. This variation is more prominent in patients with epilepsy. Decreased glucose levels may be an important physiological seizure trigger.
    Epilepsy & Behavior 04/2013; 27(3):455-460. DOI:10.1016/j.yebeh.2013.03.015 · 2.06 Impact Factor
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    • "In this regard, a genetically determined increased excitability of neuronal circuits provides an attractive explanation as to why otherwise normal individuals should develop unprovoked seizures without an identifiable focus of onset. To assess progress in connecting the molecular genetics of epilepsy to the clinic, the mechanisms associated with the range of genes now known to be related to epilepsy syndromes have been comprehensively surveyed [18] [19]. "
    Dataset: Gene Epi
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