Mutations in 3 genes SCN1A, SCN1B and GABRG2 have been shown to cause GEFS+ in families of various ethnic origins. The occurrence of mutations in these genes in 19 families of Scandinavian origin with a history of GEFS+ was studied at Ulleval University Hospital, Oslo, Norway, and centers in Denmark. Families were identified from population-based twin registries in Denmark and Norway. One mutation in SCN1A was identified in a Danish family with phenotypes consistent with GEFS+. The mutation was not found in healthy and unrelated controls. No mutations were found in any of the other families. [1]

COMMENT. GEFS+ is an autosomal dominant disorder characterized by multiple febrile seizures persisting beyond age 5 years and complicated by afebrile seizures of absence, myoclonic or atonic types. Seizures cease in mid-childhood [2, 3]. Genes on chromosomes 2q24 and 19ql3 encode subunits of the voltage-gated sodium ion channels, while the gene on 5q31 codes for the g-subunit of the g-aminobutyric acid (GABA) receptor. The genes responsible for GEFS+ show considerable heterogeneity and variable expressivity. GEFS+ is an evolving composite of many syndromes, with shared genetic susceptibility [4]. While the definition of GEFS+ is continually changing and probably involves many genes, the common denominator is the association with febrile seizures.

Failure of replication of epilepsy gene associations is discussed by researchers from Columbia University Medical Center, and New York State Psychiatric Institute, New York, NY (5). Over 50 genetic associations with various idiopathic epilepsy syndromes are reported but most have not been replicated. Genetic heterogeneity is a confounder in population-based studies, in both association and linkage studies. Linkage, association, and mutation analyses are the most common methods of evaluating candidate genes in epilepsy. The authors advocate the integration of results from different experimental methods rather than insisting only on replication.

Discovery of susceptibility genes and their association with drug responsiveness and sideeffects should permit new diagnostic and therapeutic options in the management of the epilepsies. [6]