GEFS+ reloaded. The genetics of Febrile Seizures (FS) is one big mystery. Even though large families have been reported and multiple linkage studies have been performed, no single susceptibility gene for Febrile Seizures is known. This is somehow surprising, given that FS is by far the most common epilepsy syndrome. In contrast to common FS, genetic research has been very successful in families with Genetic Epilepsy with Febrile Seizures Plus (GEFS+), where Febrile Seizures Plus (FS+) are the most striking feature in families. Ever since the definition of the GEFS+ spectrum was established, the distinction from common FS has been a matter of debate. Now a twin study in Epilepsy Research suggests FS and FS+ might actually be two very distinct diseases with little genetic overlap.
Twin, fever and epilepsy. In their recent study in Epilepsy Research, Eckhaus and collaborators review the phenotypes of twins recruited at the Epilepsy Research Centre, Melbourne, Australia. In total, the phenotypes of 76 monozygotic (identical) twin pairs and 103 dizygotic (nonidentical) were investigated. In particular, the authors looked at the type of febrile seizures and the febrile seizure syndrome. Twin studies are extremely powerful in investigating the source of phenotypic variability. Usually, for a given phenotype, the concordance is compared in identical and non-identical twins. If a trait has a genetic contribution, the MZ concordance (identical twins) is higher than the DZ concordance (non-identical twins).
Types and syndromes. Febrile seizure types are usually differentiated into simple febrile seizures, complex febrile seizures and febrile status epilepticus. Complex febrile seizures are present if the seizure has focal signs or if a second febrile occur within 24 hours. Febrile status epilepticus is present if the seizure lasts longer than 15 minutes. Febrile seizure syndromes were differentiated into “true” FS, FS+ and FS with later epilepsy. True FS were present if the individual only had febrile seizures, FS+ were present if the febrile seizures persisted past the age of six years or if afebrile seizures were also present. FS with later epilepsy referred to individuals were epilepsy (recurrent afebrile seizures) developed after the febrile seizures.
What the twins tell us. In the current study, an excess of MZ concordance was found for virtually all seizure types and syndromes. This suggests that different FS seizure types and FS syndrome have a genetic contribution. While a genetic impact on Febrile Seizures had been documented previously in several other studies, the study by Eckhaus and collaborators is the first study to include a modern definition of FS+ and a rigorous distinction of true FS from FS+. And this distinction results in a surprising finding.
FS and FS+, two diseases. When looking at the phenotypes of the concordant MZ twins pairs, i.e. the pairs of identical twins where both twins were affected, they stumbled upon an interesting observation. Even though identical twin pairs existed where one twin had FS and the other twin had FS with later epilepsy, all MZ twin pairs with FS+ were concordant. This means that if one twin had FS+, the other affected twin also had FS+. There was little variation in the FS syndrome of the other affected twin, if one twin had FS+. While this observation might partially be due to small numbers, this lack of mixed twin phenotypes is remarkable. It suggests that FS and FS+ might actually be two different disorders with little or no genetic overlap.
FS goes next gen. Both the abstract and the full article of the paper by Eckhaus and collaborators suggest that their findings might guide the design of next generation sequencing studies by emphasizing the difference between FS and FS+. This comment begs the question how the genetics of FS can be addressed most efficiently. In fact, the genetic investigations on FS on a larger scale have pretty much stopped. While many FS families are probably investigated by individual groups on a smaller scale, FS as a key phenotype are not included in the existing large research consortia on epilepsy genetics. I am wondering whether FS as common, mild epilepsy syndromes might be analyzed first using a genome-wide association study (GWAS) prior to embarking on exome or genome sequencing. If anybody would be interested in writing a grant for this, please let me know.