In light of their pioneering genetic studies on the classical idiopathic generalized epileptic syndromes (IGE), Metrakos and Metrakos concluded that “centrencephalic type of electroencephalogram is the expression of an autosomal dominant gene, with the unusual characteristic of a very low penetrance at birth, which rises rapidly to nearly complete penetrance for ages 4 to 16 and declines gradually to almost no penetrance after the age of 40 years” (1,2). More than 40 years later, despite a large body of clinical evidence incriminating hereditary factors in IGE, the mode of inheritance of these syndromes remains a matter of debate, with many linkage studies providing conflicting results (3,4,5,6). These discrepancies may reflect the fact that IGE syndromes are usually not inherited in a clearly Mendelian manner, but rather show a complex inheritance pattern. Indeed, if a concordance rate in identical twins is found in up to 95% for IGE (7,8)— suggesting an almost complete genetic etiology for this syndrome— many studies have shown a relatively small increased risk of epilepsy in first- (13%) and second-degree (6%) relatives (2,9,10) for epilepsy per se. Based on this rapid decrease in the risk of epilepsy with each degree of relationship, many authors suggested that IGE could be caused by a multiplicative (epistatic) interaction among many contributing loci (polygenic model) (8). In addition, various environmental factors (e.g., sleep deprivation, alcohol and drug abuse, head trauma) can also increase the risk of developing epilepsy, including IGE (11). However, these epidemiologic studies probably represent a crude approximation of a very complex reality. First, because of sociocultural factors, the family history of epilepsy is often unknown to the proband and immediate family, and a systematic survey of all family members is often required to find additional affected individuals within the same family (1,2,12). In addition, these studies lumped all the IGE together, even though these syndromes have been shown to be clinically, and genetically highly heterogeneous. In particular, these studies do not take into consideration the recent studies of the large kindreds with idiopathic epilepsy, where an autosomal dominant (or recessive) mode of inheritance has been demonstrated (Table 19-1). Finally, the clinical assessment itself, even by experienced clinicians, is not simple, mainly because of the variable expression of the disease during lifetime, as well as the occurrence of many intermediate phenotypes. Therefore, the current state of knowledge indicates that IGE is clearly not a single entity, but rather represents the sum of a large variety of different genetic diseases: some being clearly Mendelian traits, while others exhibiting polygenic inheritance.