A number sign (#) is used with this entry because of evidence that susceptibility to generalized epilepsy with febrile seizures plus, type 5 (GEFSP5) can be conferred by variation in the GABRD gene (137163) on chromosome 1p36. One such family has been reported.

Idiopathic generalized epilepsy (EIG; see 600669) is a broad term that encompasses several common seizure phenotypes, classically including childhood absence epilepsy (CAE, ECA), juvenile absence epilepsy (JAE), and juvenile myoclonic epilepsy (JME, EJM) (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). Generalized epilepsy with febrile seizures plus (GEFS+) shows phenotypic overlap with EIG, and includes patients with early-onset febrile seizures who later develop various types of febrile and afebrile seizures, such as those observed in EIG (summary by Singh et al., 1999).

For a general phenotypic description and a discussion of genetic heterogeneity of GEFS+, see 604233.

Dibbens et al. (2004) screened 72 unrelated patients with idiopathic generalized epilepsy, 65 with GEFS+, and 66 with febrile seizures for mutations in the GABRD gene. Two informative families were identified: 1 had a phenotype consistent with GEFS+ and the other with juvenile myoclonic epilepsy, which is a subtype of EIG.

Dibbens et al. (2004) screened 72 unrelated patients with idiopathic generalized epilepsy, 65 with GEFS+, and 66 with febrile seizures for mutations in the GABRD gene. Affected members of a small family with GEFS+ had a heterozygous mutation (E177A; 137163.0001). A heterozygous polymorphism in the GABRD gene (R220H; 137163.0002) was associated with different forms of epilepsy: the polymorphism was identified in 8.3% of patients with idiopathic generalized epilepsy and 3.1% with GEFS+, but also in 4.2% of control individuals. One individual with juvenile myoclonic epilepsy (JME), designated EJM7, was homozygous for the R220H mutation and her daughter with JME was heterozygous for the mutation; however, a third affected family member was unavailable for testing. Both of these alterations resulted in decreased GABA-A receptor current amplitudes. Since GABA-A receptors mediate neuronal inhibition, Dibbens et al. (2004) hypothesized that reduced receptor current associated with both variants may be associated with increased neuronal excitability and may contribute to the common generalized epilepsies. Dibbens et al. (2004) emphasized, however, that these variants are likely only a small component of a multifaceted system of rare variants and polymorphisms that contribute to increased susceptibility to common epilepsies.

In contrast to the findings of Dibbens et al. (2004), Lenzen et al. (2005) found no association between the GABRD R220H variant and idiopathic generalized epilepsy or juvenile myoclonic epilepsy among 562 German patients and 664 controls. Hamosh (2024) noted that the R220H variant was present in 4,871 of 279,648 alleles and in 55 homozygotes in the gnomAD database (v2.1.1), with an allele frequency of 0.01742. The variant was reclassified as a polymorphism.