Other entities represented in this entry:
ORPHA: 36387, 64280; DO: 0111298;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q34 | Generalized epilepsy with febrile seizures plus, type 3 | 607681 | Autosomal dominant | 3 | GABRG2 | 137164 |
| 5q34 | Febrile seizures, familial, 8 | 607681 | Autosomal dominant | 3 | GABRG2 | 137164 |
A number sign (#) is used with this entry because of evidence that familial febrile seizures-8 (FEB8) is caused by heterozygous mutation in the GABRG2 gene (137164) on chromosome 5q34.
Mutations in the GABRG2 gene cause a spectrum of seizure disorders, ranging from early-onset isolated febrile seizures (FS) to childhood absence epilepsy (CAE) to generalized epilepsy with febrile seizures plus, type 3 (GEFS+3), which tends to represent a more severe phenotype. Patients with isolated febrile seizures usually have onset in the first year of life and show spontaneous remission by age 6 years. Many of these patients may later develop absence seizures, which may also spontaneously remit, whereas a few may continue to have various types of febrile and afebrile seizures that persist beyond childhood, consistent with GEFS+. There is phenotypic variability in the seizure type, even within a family carrying the same mutation, suggesting that other loci may be involved (summary by Singh et al., 1999 and Marini et al., 2003).
For a phenotypic description and a discussion of genetic heterogeneity of familial febrile seizures, see 121210.
For a general phenotypic description and a discussion of genetic heterogeneity of GEFS+, see 604233.
For a phenotypic description and discussion of genetic heterogeneity of childhood absence epilepsy, see 600131.
Baulac et al. (2001) studied a large 3-generation French family in which 8 members had only febrile seizures, 3 had febrile and afebrile seizures, and 2 had afebrile seizures. All 13 of these individuals carried a heterozygous missense GABRG2 mutation (K289M; 137164.0001). In addition, there were 3 unaffected mutation carriers and 1 patient with afebrile seizures who did not carry the mutation.
Wallace et al. (2001) reported a large 4-generation Australian family segregating various forms of epilepsy, mainly febrile seizures and childhood absence seizures. Several patients had unclassified forms of epilepsy and 3 had febrile seizures-plus. The authors noted that FS and CAE have different ages of onset, and that the physiology of each is distinct. However, all affected individuals were found to have the same mutation in the GABRG2 gene (R43Q; 137164.0002). The findings suggested that the mutation has age-dependent effects on different neuronal networks that influence the expression of these clinically distinct, but genetically related, epilepsy phenotypes. In the second generation, there were several reportedly unaffected mutation carriers, which may have indicated either poor history or incomplete penetrance. Wallace et al. (2001) also stated that febrile seizures occur in about 3% of children and that 10 to 15% of persons with childhood absence epilepsy have febrile seizures before the onset of epilepsy. Febrile seizures are a common seizure type in relatives of childhood absence epilepsy probands (Italian League Against Epilepsy Genetic Collaborative Group, 1993).
Marini et al. (2003) reported follow-up of the family reported by Wallace et al. (2001), which included 35 members with seizures (34 patients were listed in table 1), 25 of whom were shown to carry the R43Q mutation. Fifteen patients had febrile seizures only, whereas 8 had typical absence seizures, including 6 who had febrile seizures prior to the onset of absence seizures. Nine patients with either FS or CAE also had generalized tonic-clonic seizures. Five of the 8 with CAE had an EEG that showed typical 3-Hz spike-wave activity, although 1 of these patients did not carry the mutation, suggesting a phenocopy; this patient also did not have febrile seizures, but did have a learning disability. There were 3 patients with GEFS+, defined as febrile and afebrile seizures or persistence of seizures after age 6 years; only 1 of these patients had learning disabilities. Two mutation carriers with myoclonic-astatic epilepsy had learning disabilities and borderline intellectual function. Four patients with only febrile seizures were not genetically tested, and 2 with afebrile seizures and 1 with an abnormal EEG did not carry the mutation. Marini et al. (2003) concluded that the complex seizure phenotype and segregation/inheritance pattern in this family suggested that a second locus, besides GABRG2, may contribute to the phenotype. In particular, they suggested that the GABRG2 mutation contributes to febrile seizures, but that the CAE phenotype may be due to a combined effect of the GABRG2 mutation and another unidentified mutation.
Kananura et al. (2002) reported a German family in which the father had isolated febrile convulsions as a child, but his 2 children had both febrile seizures and childhood absence epilepsy. All 3 had the same heterozygous truncation mutation in the GABRG2 gene (137164.0004). The findings indicated that in some families there is a phenotypic spectrum of childhood absence epilepsy and febrile convulsions with a similar underlying genetic defect.
Audenaert et al. (2006) reported a family in which 2 sibs and their father had isolated febrile seizures. Age at onset was between 13 and 18 months, and seizures resolved in all 3 patients by age 5 years. Mental development was normal, and epilepsy did not develop later in life. Molecular analysis identified a heterozygous mutation in the GABRG2 gene (R139G; 137164.0005) in all 3 patients. The paternal grandfather, who was reportedly unaffected, also carried the mutation, suggesting incomplete penetrance.
Carvill et al. (2013) reported a 2.5-year-old boy with generalized epilepsy with febrile seizures plus. He had onset of febrile seizures at age 8 months, followed by absence seizures, atonic seizures, myoclonic jerks, and tonic-clonic seizures. EEG was normal and he had normal development. Genetic analysis identified a de novo heterozygous mutation in the GABRG2 gene (R323Q; 137164.0006). The patient was ascertained from a large cohort of 500 patients with epileptic encephalopathy who underwent candidate gene sequencing; this was the only patient found to carry a GABRG2 mutation.
The transmission pattern of febrile seizures in the family reported by Wallace et al. (2001) was consistent with autosomal dominant inheritance and incomplete penetrance.
In affected members of a family with FEB8, Baulac et al. (2001) identified a heterozygous mutation in the GABRG2 gene (K289M; 137164.0001). The mutation affected a highly conserved residue located in the extracellular loop between transmembrane segments M2 and M3. Analysis of the mutated and wildtype alleles in Xenopus laevis oocytes confirmed the predicted effect of the mutation, a decrease in the amplitude of GABA-activated currents.
In affected members of a large 4-generation Australian family with FEB8, Wallace et al. (2001) identified a heterozygous missense mutation in the GABRG2 gene (R43Q; 137164.0002).
In a German family in which the father had isolated febrile convulsions as a child, but his 2 children had both febrile seizures and childhood absence epilepsy (ECA2), Kananura et al. (2002) identified a heterozygous truncating mutation in the GABRG2 gene (137164.0004).
In a mother and son with FEB8, Harkin et al. (2002) identified a heterozygous nonsense mutation in the GABRG2 gene (Q351X; 137164.0003). The mother also had a daughter who carried the mutation but had a phenotype consistent with severe myoclonic epilepsy of infancy, as well as a son with myoclonic astatic-epilepsy (MAE) who did not carry the mutation. There was also another family member with febrile seizures who did not carry the mutation. Another branch of the family had individuals with severe febrile seizures, but genetic studies were not performed. The family, which had previously been described as 'family G' by Singh et al. (1999), had a complex seizure phenotype from both the maternal and paternal side, but not all affected individuals were studied genetically.
Tan et al. (2007) found that mice homozygous for the Gabrg2 R43Q mutation (137164.0002) were rarely viable. Those that survived the perinatal period showed altered gait, severe tremor, and death by postnatal day 19. Heterozygous mice showed behavioral arrest associated with 6 to 7 Hz spike-and-wave discharges, which could be blocked by ethosuximide, a first-line treatment for absence epilepsy in humans. Seizures in the mouse showed an abrupt onset at around age 20 days, which corresponds to the childhood nature of this disease in humans. Brain tissue from R43Q-mutant mice showed impaired inhibitory activity specifically in the somatosensory cortex, as well as decreased expression of the mutant protein. There was no change in alpha-1 subunit expression, ruling out a dominant-negative effect. Tan et al. (2007) hypothesized that a subtle reduction in cortical inhibition, resulting from haploinsufficiency, underlies childhood absence epilepsy seen in humans with the R43Q mutation.
Audenaert, D., Schwartz, E., Claeys, K. G., Claes, L., Deprez, L., Suls, A., Van Dyck, T., Lagae, L., Van Broeckhoven, C., Macdonald, R. L., De Jonghe, P. A novel GABRG2 mutation associated with febrile seizures. Neurology 67: 687-690, 2006. [PubMed: 16924025] [Full Text: https://doi.org/10.1212/01.wnl.0000230145.73496.a2]
Baulac, S., Huberfeld, G., Gourfinkel-An, I., Mitropoulou, G., Beranger, A., Prud'homme, J.-F., Baulac, M., Brice, A., Bruzzone, R., LeGuern, E. First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma-2-subunit gene. Nature Genet. 28: 46-48, 2001. [PubMed: 11326274] [Full Text: https://doi.org/10.1038/ng0501-46]
Carvill, G. L., Heavin, S. B., Yendle, S. C., McMahon, J. M., O'Roak, B. J., Cook, J., Khan, A., Dorschner, M. O., Weaver, M., Calvert, S., Malone, S., Wallace, G., and 22 others. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nature Genet. 45: 825-830, 2013. [PubMed: 23708187] [Full Text: https://doi.org/10.1038/ng.2646]
Harkin, L. A., Bowser, D. N., Dibbens, L. M., Singh, R., Phillips, F., Wallace, R. H., Richards, M. C., Williams, D. A., Mulley, J. C., Berkovic, S. F., Scheffer, I. E., Petrou, S. Truncation of the GABA-A-receptor gamma-2 subunit in a family with generalized epilepsy with febrile seizures plus. Am. J. Hum. Genet. 70: 530-536, 2002. [PubMed: 11748509] [Full Text: https://doi.org/10.1086/338710]
Italian League Against Epilepsy Genetic Collaborative Group. Concordance of clinical forms of epilepsy in families with several affected members. Epilepsia 34: 819-826, 1993. [PubMed: 8404731] [Full Text: https://doi.org/10.1111/j.1528-1157.1993.tb02096.x]
Kananura, C., Haug, K., Sander, T., Runge, U., Gu, W., Hallmann, K., Rebstock, J., Heils, A., Steinlein, O. K. A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. Arch. Neurol. 59: 1137-1141, 2002. [PubMed: 12117362] [Full Text: https://doi.org/10.1001/archneur.59.7.1137]
Marini, C., Harkin, L. A., Wallace, R. H., Mulley, J. C., Scheffer, I. E., Berkovic, S. F. Childhood absence epilepsy and febrile seizures: a family with a GABA-A receptor mutation. Brain 126: 230-240, 2003. [PubMed: 12477709] [Full Text: https://doi.org/10.1093/brain/awg018]
Olsen, R. W., DeLorey, T. M., Gordey, M., Kang, M. H. GABA receptor function and epilepsy. Adv. Neurol. 79: 499-510, 1999. [PubMed: 10514838]
Singh, R., Scheffer, I. E., Crossland, K., Berkovic, S. F. Generalized epilepsy with febrile seizures plus: a common childhood-onset genetic epilepsy syndrome. Ann. Neurol. 45: 75-81, 1999. [PubMed: 9894880] [Full Text: https://doi.org/10.1002/1531-8249(199901)45:1<75::aid-art13>3.0.co;2-w]
Tan, H. O., Reid, C. A., Single, F. N., Davies, P. J., Chiu, C., Murphy, S., Clarke, A. L., Dibbens, L., Krestel, H., Mulley, J. C., Jones, M. V., Seeburg, P. H., Sakmann, B., Berkovic, S. F., Sprengel, R., Petrou, S. Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy. Proc. Nat. Acad. Sci. 104: 17536-17541, 2007. [PubMed: 17947380] [Full Text: https://doi.org/10.1073/pnas.0708440104]
Wallace, R. H., Marini, C., Petrou, S., Harkin, L. A., Bowser, D. N., Panchal, R. G., Williams, D. A., Sutherland, G. R., Mulley, J. C., Scheffer, I. E., Berkovic, S. F. Mutant GABA(A) receptor gamma-2-subunit in childhood absence epilepsy and febrile seizures. Nature Genet. 28: 49-52, 2001. [PubMed: 11326275] [Full Text: https://doi.org/10.1038/ng0501-49]