Reza Behrouz Selim R Benbadis
Idiopathic generalized epilepsies £ (IGEs) are a distinct group of epi-^^ lepsies, clearly defined in the 1989 International Classification of Epileptic Syndromes and Epilepsies. This classification established an important dichotomy between the idiopathic epilepsies on the one hand, and the symptomatic or cryp-togenic epilepsies on the other (1). In prior versions of this classification, IGEs were referred to as primary generalized epilepsies, and symptomatic/cryptogenic generalized epilepsies were categorized under secondary generalized epilepsies. This nomenclature was revised because the term "secondary generalized" was confusing when applied to epilepsy, where it meant that the epilepsy was secondary to some other cause, whereas when applied to seizures, it means that the generalization is secondary from an originally focal seizure.
Unfortunately, the term "idiopathic" in the current classification is also confusing in the context of current medical terminology, because in every other area of medicine "idiopathic" means "of an unknown cause." It is now clearly understood that IGEs are primarily of genetic origin.
IGEs are age-dependent, meaning that a given genotype may express itself differently at different ages. This chapter will focus on the IGE seen in adolescence.
GENETICS & PATHOPHYSIOLOGY
IGEs represent a group of epilepsies best described as a genetically determined low threshold for generalized seizures, as opposed to symptomatic or cryptogenic generalized epilepsies, where there is an underlying anatomic (pathologic) abnormality. Investigations for microscopic lesions (e.g., microdysgenesis) in IGE, using structural imaging, have yielded inconsistent results (2). Functional imaging, not surprisingly, can show evidence for diffuse dysfunction. Proton magnetic resonance spectros-copy (MRS) has revealed frontal lobe (3) or thalamic (4) abnormalities.
Because they have "overlapping" genetic origins, it is appropriate and practical to view IGEs as a continuum of genetic conditions exhibiting variable phenotypes. Recent advances have identified IGEs linked to defects in genes encoding the subunits for voltage- or ligand-gated ion channels including sodium, potassium, calcium, or chloride channels affecting the gamma-aminobutyric acid (GABA)A receptors. Hence, they are categorically referred to as "ion channelopathies" (5). For the classic and well-defined forms of IGE—juvenile myoclonic epilepsy (JME) or childhood absence epilepsy (CAE), a few mutations, including the KCNQ potassium channels and the ClC-2 chloride channel, have been implicated (6).
The pathophysiology (e.g., the concept of channelopa-thies) and genetics of IGE are gradually being elucidated. Fundamentally, IGEs appear to be "phenotypes of many, often individually rare, gene defects" (7, 8).
The inheritance of IGEs is complex in the sense that it does not follow a well-defined Mendelian pattern. Moreover, phenotypic expression influencing semiology and frequency of a specific genotype may be quite variable from one individual to another. This is likely due to different degrees of alteration of neuronal excitability induced by gene errors. At least for JME, a maternal inheritance has been proposed and confirmed by some (9). Nevertheless, it is reasonable to state that the genetic complexity of IGEs necessitates additional investigation in order to reach a conclusion regarding their precise mechanism of inheritance.
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