Although the first identification of a channel gene mutation in epilepsy occurred only in 1994, many such mutations have now been identified in 15 different channel subunits and channel-associated proteins. What do these efforts reveal about the causes of epilepsy and potential for novel treatments? One remarkable result is that many of the mutations have been found in subunits of voltage-dependent Na+ channels and GABA receptors, important targets of the majority of currently approved drugs, all developed through in vivo pharmacologic screening. Many (but not all) Na+ channel mutations in GEFS + , for example, result in increased Na+ channel activity; by contrast, such drugs as phenytoin, carbamazepine, and lamotrigine act by blocking Na+ channel activity. Similarly, in autosomal dominant JME and some cases of GEFS + , mutations in GABA receptor subunits that reduce activity are implicated, whereas benzodiazepines and barbiturates potentiate GABA receptor activity. This is satisfying, but is also potentially a cause for concern. If genetics were only to lead us back to the therapeutic targets we know about, it would be informative but of little practical use. In this regard, the stories of the identification of the KCNQ channel mutations in BFNS, nicotinic acetylcholine receptor mutations in ADNFLE, and Lgi1 mutations in ADPEAF are exciting and reassuring counterexamples. The neuronal KCNQ channels and the functions of Lgi1 regulating K+ channels and glutamate receptors were unknown before these mutations led to the recent mechanistic studies discussed in this chapter. It seems possible that a new class of KCNQ opener drugs may be developed, with patterns of clinical usefulness that are quite different from available agents. The Lgi1-dependent augmentation of K+ channel activity is another potential target for future drug development. As neuro-biologic studies allow us to understand the mechanistic pathways through which individual mutations lead to seizures, additional targets will be revealed beyond the mutated gene itself. An example of this is the unexpected observation that nicotinic receptor mutations in ADNFLE may cause seizures through enhanced inhibition during arousal from deep sleep. Interestingly, low doses of pic-rotoxin, a GABA antagonist that is strongly convulsant at higher doses, blocked epileptiform EEG activity and spontaneous seizures in transgenic mice bearing ADNFLE mutations (116).
Although many aspects of genotype-phenotype relationships remain poorly understood, recent years have brought considerable progress, encouraging optimism that the pathogenic mechanisms in these disorders can be understood in detail. Examples of such progress are the identification of the role for KCNQ channels in setting thresholds by targeting to the axonal spike initiation zone, the discovery that SCN1A subunits are preferentially expressed on inhibitory interneurons, and the analysis showing how KCNM1 mutations increasing the activity of BK channels can paradoxically increase neuronal excitability (30, 81, 155). However, it remains unclear whether, in GEFS+ families, the variable phe-notype seen within pedigrees may reflect differences in genetic background between individuals, environmental exposures, or both. The spectrum of phenotypes associated with SCN1A mutations, ranging from normal gene carriers or patients with only FS in GEFS+ pedigrees to SMEI patients with severe refractory seizures and progressive motor and cognitive decline, is impressive and requires further study. It remains unclear whether the more severe phenotypes in GEFS+ pedigrees and SMEI should be seen as a part of the GEFS+ spectrum, since they are almost certainly associated with secondary changes in brain structure and function (e.g., cell death, network reorganization, changes in the levels of expression of other channels and signaling proteins) that do not occur in mildly affected individuals. Finally, as pathogenic mechanisms in these Mendelian forms of epilepsy become clearer, efforts will focus on understanding to what extent these mechanisms contribute to the common, non-Mendelian forms of epilepsy. Already, the epileptic channelopathies fit poorly with our traditional classification of the epilepsies as idiopathic (i.e., hereditary, with normal function except for seizures) versus symptomatic (associated with cognitive, motor, and other deficits). Not only can different mutations in the same channel cause varying degrees of impairment—the same mutation can have variable effects within a pedigree.
Resolving these and unforeseen questions arising with the identification of novel epilepsy mutations should be extremely fruitful both in terms of a better understanding of basic mechanisms underlying seizures and epileptogenesis and for drug development.
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