Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Generalized Epilepsy with Febrile Seizures Plus (GEFS+) [G40.3]

OMIM numbers: 300088300460 (PCDH19)

Dr. rer. nat. Karin Mayer

Scientific Background

Generalized epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant epilepsy syndrome marked by high phenotypical variability within one family. Febrile seizures, occurring also after the sixth year of life as well as fever-independent, generalized tonic clonic epilepsy associated with absences, myoclonic, atonic or focal seizures are characteristic.

With a percentage of 10-20 of all cases, mutations in SCN1A, which encodes the α1 subunit of a neuronal sodium channel, are the most common cause of GEFS+. They are usually amino acid substitutions in the SCN1A gene and may be the cause of both GEFS+ as well as severe myoclonic epilepsy in infancy (SMEI); missense mutations in the pore region of the sodium channel, however, have been more frequently associated with severe SMEI. Besides SCN1A mutations, mutations in two other genes have been described in GEFS+ for neuronal voltage-gated sodium channels (SCN1B and SCN2A) as well as in the genes for the γ2 subunit and the δ subunit of the GABA receptor (GABRG2 and GABRD). Mutations in SCN1B, which encodes the β1 subunit of a neuronal sodium channel, have been described in only seven families with GEFS+. The six mutations that have so far been described in the GABRG2 gene, which encodes the γ2 subunit of the GABA receptor, are the cause of the disease in approximately 1% of all examined patients suffering from GEFS+ or childhood absence epilepsy with febrile seizures. Mutations in SCN2A, which encodes the α2 subunit of a neuronal sodium channel, play only a minor role in GEFS+, as missense mutations have so far only been described in single cases, while all other SCN2A mutations were identified in patients with benign familial neonatal-infantile epilepsy. The combined mutation detection rate in GEFS+ for all five genes is 8-17%.

Mutations in the gene for protcadherin 9 (PCDH19 on chromosome Xq22) were described in female patients with X-bound epilepsy and mental disability. Similar to overlapping signs and symptoms in patients suffering from Dravet syndrome with SCN1A mutations and PCDH19 mutations, PCDH19 mutations have been identified in GEFS+ patients as well. The frequency of PCDH19 mutations in patients with GEFS+ is unknown.