history of FS may have been underreported in this generation. The relatively high frequency (5.6%) of GABRG2 mutations compared with previously published data24,28,30 is most probably linked to the fact that FS segregating as an autosomal dominant trait was a study inclusion criterion. Additional genetic or epigenetic modifiers probably determine the associated epilepsy component, which can result either in no subsequent epilepsy or in the development of both generalized and focal seizures. Consistent with this hypothesis, 2 Gabrg2 knock-in (p.Arg82Gln) mouse models established in 2 different mouse strains exhibited similar temperature-seizure susceptibilities, mimicking the FS phenotype, whereas the epilepsy phenotype was only present in 1 strain.33 This suggested that FS are less sensitive to genetic background than the associated epileptic phenotypes. An emerging question is how to explain the link between FS and GABAergic defects. Reports have shown that the GEFS+-causing mutation p.Lys328Met affects the membrane dynamics and postsynaptic aggregation of the GABAA mutant receptor in conditions of increased temperature, confirming the susceptibility to temperature.6,34,35
