Generalized epilepsy with febrile seizures plus (GEFS+): clinical spectrum in seven Italian families unrelated to SCN1A, SCN1B, and GABRG2 gene mutations.
OBJECTIVE
We describe seven Italian families with generalized epilepsy with febrile seizures plus (GEFS+), in which mutations of SCN1A, SCN1B, and GABRG2 genes were excluded and compare their clinical spectrum with that of previously reported GEFS+ with known mutations.


METHODS
We performed a clinical study of seven families (167 individuals). The molecular study included analysis of polymerase chain reaction (PCR) fragments of SCN1A and SCN1B exons by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing of GABRG2 in all families. We excluded SCN1A, SCN1B, and GABRG2 genes with linkage analysis in a large pedigree and directly sequenced SCN2A in a family with neonatal-infantile seizures onset. We compared the epilepsy phenotypes observed in our families with those of GEFS+ families harboring mutations of SCN1A, SCN1B, and GABRG2 and estimated the percentage of mutations of these genes among GEFS+ cases by reviewing all published studies.


RESULTS
Inheritance was autosomal dominant with 69% penetrance. Forty-one individuals had epilepsy: 29 had a phenotype consistent with GEFS+; seven had idiopathic generalized epilepsy (IGE); in three, the epilepsy type could not be classified; and two were considered phenocopies. Clinical phenotypes included FS+ (29.2%), FS (29.2%), IGE (18.2%), FS+ with focal seizures (13%) or absence seizures (2.6%), and FS with absence seizures (2.6%). Molecular study of SCN1A, SCN2A, SCN1B, and GABRG2 did not reveal any mutation. Results of our study and literature review indicate that mutations of SCN1A, SCN2A, SCN1B, and GABRG2 in patients with GEFS+ are rare.


CONCLUSIONS
The most frequently observed phenotypes matched those reported in families with mutations of the SCN1A, SCN1B, and GABRG2 genes. IGE and GEFS+ may overlap in some families, suggesting a shared genetic mechanism. The observation that 13% of affected individuals had focal epilepsy confirms previously reported rates and should prompt a reformulation of the "GEFS+" concept to include focal epileptogenesis.
Bonanni
Paolo
P
Epilepsy, Neurophysiology, Neurogenetics Unit, IRCCS Fondazione Stella Maris, Pisa, Italy.
Malcarne
Michela
M
Moro
Francesca
F
Veggiotti
Pierangelo
P
Buti
Daniela
D
Ferrari
Anna Rita
AR
Parrini
Elena
E
Mei
Davide
D
Volzone
Anna
A
Zara
Federico
F
Heron
Sarah E
SE
Bordo
Laura
L
Marini
Carla
C
Guerrini
Renzo
R
D000293:Adolescent; D000328:Adult; D002648:Child; D004828:Epilepsies, Partial / Q000235:genetics; D004832:Epilepsy, Absence / Q000235:genetics; D004829:Epilepsy, Generalized / Q000235:genetics*; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011963:Receptors, GABA-A / Q000235:genetics*; D003294:Seizures, Febrile / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics*; D062547:Voltage-Gated Sodium Channel beta-1 Subunit
C546279:GABRG2 protein, human; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D011963:Receptors, GABA-A; C568242:SCN1A protein, human; C470379:SCN1B protein, human; C568251:SCN2A protein, human; D015222:Sodium Channels; D062547:Voltage-Gated Sodium Channel beta-1 Subunit