A childhood-onset, genetic epilepsy syndrome, recently described in a single Australian family and characterized as “generalized epilepsy with febrile seizures plus” (GEFS+), is reported in an additional 63 patients from 9 families evaluated at the University of Melbourne, Australia. Examination of the phenotypic variation and clinical genetics of the syndrome among these patients showed simple febrile seizures, occurring only with fever between 3 months and 6 years of age (FS), in 31 (50%) patients, complicated febrile seizures that continued beyond 6 years of age or were associated with afebrile tonic-clonic seizures (FS+) in 15 (24%), and FS+ with other seizure types (atonic, myoclonic, absence, complex partial or myoclonic-astatic) in 17 (27%). Most patients with GEFS+ had benign self-limited epilepsies, normal neurological development, and generalized spike-wave or polyspike-wave discharges in the EEG. Inheritance was autosomal dominant with 60% penetrance. Heterogeneity of phenotypes within families is the hallmark of the syndrome. GEFS+ in one family was linked to chromosome 19q, with a mutation in the B1 subunit of the neuronal sodium channel. [1]

COMMENT. In a child with familial, recurrent febrile seizures (FS) that persist beyond 6 years of age and are complicated by generalized afebrile epilepsies, a diagnosis of the autosomal dominant, generalized epilepsy with febrile seizures plus syndrome (GEFS+) should be considered and genetic analysis attempted. Compared to the typical febrile seizure syndrome, with no recurrences after 6 years, GEFS+ syndrome has a less favorable prognosis, with afebrile epilepsies persisting into mid-adolescence or even adult life.

The inheritance of FS is multifactorial . Siblings have an 8-12% risk of also having FS. If the index child and one parent are affected, the risks to siblings are 30-40% (50% if both parents are affected). (See [2], reviewed in Progress in Pediatric Neurology I. PNB Publ, 1991;ppl5-16). In my own series of FS patients, a family history of FS is found in 17% of cases. The incidence is similar in those complicated by nonfebrile seizures, and an inherited tendency to nonfebrile seizures is equally prevalent. Recurrent nonfebrile seizures, especially generalized tonic-clonic epilepsy, among children with FS are reported in 20% (average) of 4500 patients in 35 publications between 1929 and 1964 . The average familial incidence of epilepsy in the total was 15%. Analyses of these case reports suggest that the genetically determined factors that may result in a low threshold to FS are associated with an equally prevalent genetic predisposition to nonfebrile seizures [3]. These previous reports are in agreement with the concept of the GEFS+ syndrome, and families identified warrant genetic analysis.