Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 36803009; ICD10CM: G40.3, G40.309; DO: 1827;
Cytogenetic location: 8q24 Genomic coordinates (GRCh38): 8:116,700,001-145,138,636
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q24 | {Epilepsy, idiopathic generalized, susceptibility to, 1} | 600669 | Autosomal dominant | 2 |
Idiopathic generalized epilepsy is a broad term that encompasses several common seizure phenotypes, classically including childhood absence epilepsy (CAE, ECA; see 600131), juvenile absence epilepsy (JAE, EJA; see 607631), juvenile myoclonic epilepsy (JME, EJM; see 254770), and epilepsy with grand mal seizures on awakening (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). These recurrent seizures occur in the absence of detectable brain lesions and/or metabolic abnormalities. Seizures are initially generalized with a bilateral, synchronous, generalized, symmetrical EEG discharge (Zara et al., 1995; Lu and Wang, 2009).
See also childhood absence epilepsy (ECA1; 600131), which has also been mapped to 8q24. Of note, benign neonatal epilepsy 2 (EBN2; 121201) is caused by mutation in the KCNQ3 gene (602232) on 8q24.
Genetic Heterogeneity of Idiopathic Generalized Epilepsy
EIG1 has been mapped to chromosome 8q24. Other loci or genes associated with EIG include EIG2 (606972) on 14q23; EIG3 (608762) on 9q32; EIG4 (609750) on 10q25; EIG5 (611934) on 10p11; EIG6 (611942), caused by mutation in the CACNA1H gene (607904) on 16p; EIG7 (604827) on 15q14; EIG8 (612899), caused by mutation in the CASR gene (601199) on 3q13.3-q21; EIG9 (607682), caused by mutation in the CACNB4 gene (601949) on 2q23; EIG10 (613060), caused by mutation in the GABRD gene (137163) on 1p36; EIG11 (607628), caused by variation in the CLCN2 gene (600570) on 3q36; EIG12 (614847), caused by mutation in the SLC2A1 gene (138140) on 1p34; EIG13 (611136), caused by mutation in the GABRA1 gene (137160) on 5q34; EIG14 (616685), caused by mutation in the SLC12A5 gene (606726) on 20q12; EIG15 (618357), caused by mutation in the RORB gene (601972) on 9q22; EIG16 (618596), caused by mutation in the KCNMA1 gene (600150) on chromosome 10q22; EIG17 (602477), caused by mutation in the HCN2 gene (602781) on chromosome 19p13.3; and EIG18 (619521) caused by mutation in the HCN4 gene (605206) on chromosome 15q24.
Choi et al. (2006) developed a classification tool for partial epilepsy, termed the Partial Seizure Symptom Definitions (PSSD), to more precisely phenotype individuals for genetic research in epilepsy. The PSSD includes standardized and specific definitions of 41 partial seizure symptoms within the sensory, autonomic, aphasic, psychic, and motor categories. The aim was to encourage researchers to use the PSSD to evaluate associations between partial seizure symptoms and epilepsy susceptibility genes.
McCorry et al. (2006) found an association between idiopathic generalized epilepsy and type I diabetes (IDDM; 222100) in a population-based survey in the U.K. Among 518 EIG patients aged 15 to 30 years, 7 also had IDDM. In contrast, there were 465 IDDM patients among an age-matched cohort of 150,000 individuals. The findings suggested that the prevalence of IDDM is increased in patients with EIG (odds ratio of 4.4).
In a population-based case-control study of 140 Icelandic children with seizures and 180 controls, Ludvigsson et al. (2006) found that migraine with aura (157300) conferred an odds ratio of 8.1 for subsequent development of unprovoked seizures. Migraine without aura did not increase the risk for seizures. The prevalence of both types of migraine was 20.2% in children with seizures and 6.9% in controls. The findings were consistent with the hypothesis that migraine with aura and migraine without aura are separate disease entities, and suggested that migraine with aura and seizures may share a common pathogenesis.
Empirical risk numbers observed in families with EIG are compatible with an oligogenic rather than a monogenic mode of inheritance. The complex pattern of inheritance in EIG suggests an interaction of several susceptibility genes, such that polymorphisms in multiple different susceptibility genes additively contribute to the disorder (Steinlein, 2004; Lu and Wang, 2009; Saint-Martin et al., 2009).
Twin and family studies suggest that genetic factors play a key part in the etiology of idiopathic generalized epilepsy. Berkovic et al. (1998) studied 253 twin pairs in whom one or both had seizures. The casewise concordances for generalized epilepsies were 0.82 in monozygotic twin pairs and 0.26 in dizygotic twin pairs. Lower degrees of concordance were observed in partial epilepsies with intermediate values seen for febrile seizures. In 94% of concordant monozygotic pairs, both twins had the same major epilepsy syndrome. A multilocus model may best fit the observed familial patterns.
Winawer et al. (2003) studied 84 persons from 31 families with myoclonic or absence seizures and found that 65% (20 families) were concordant for seizure type (myoclonic, absence, or both). In 2 families, all affected members had myoclonic seizures; in 12 families, all affected members had absence seizures; in 2 families, all affected members had myoclonic and absence seizures. The number of families concordant for JME was greater when compared to JAE and CAE, but not when JAE was compared to CAE. Winawer et al. (2003) concluded that there are distinct genetic effects on absence and myoclonic seizures, and suggested that examining seizure types as opposed to syndromes may be more useful in linkage studies.
Winawer et al. (2005) found concordance for seizure type, either myoclonic, absence, or both, in 23 (58%) of 40 Australian families with seizures, which was significantly higher than expected by chance alone. The findings confirmed the results of Winawer et al. (2003) that there are likely distinct genetic effects on absence and myoclonic seizures. Similarly, the authors observed clustering of generalized tonic-clonic seizures in families in which members had different forms of IGE, suggesting a specific genetic influence on the occurrence of generalized tonic-clonic seizures within IGE.
Zara et al. (1995) used nonparametric methods to study idiopathic generalized epilepsy in 10 affected families. They obtained evidence for involvement of a locus at 8q24, close to the marker D8S256 (p = 0.0003).
By exome sequencing of 237 ion channel subunit genes in 152 individuals with idiopathic epilepsy and 139 healthy controls, Klassen et al. (2011) drew 3 major conclusions: the architecture of ion channel variation in both patients and controls consists of highly complex patterns of common and rare alleles; structural variants in both known and suspected epilepsy genes are present in otherwise healthy individuals; and individuals with epilepsy typically carry more than 1 mutation in known human epilepsy genes. This genetic heterogeneity suggested that causality in most cases cannot be assigned to any particular variant, but rather results from a personal channel variant pattern, indicating an oligogenic mechanism. Because of the overlapping voltage dependence of these channels, even noninteracting channel proteins may modulate one another to affect transmembrane potential and disease pathogenesis.
Associations Pending Confirmation
In a patient with childhood absence epilepsy evolving to juvenile myoclonic epilepsy, consistent with EIG, Moore et al. (2001) identified a de novo heterozygous variation in the JRK gene (T456M; 603210). No functional studies were reported. The authors suggested that variation in the JRK gene may be a rare cause of epilepsy.
Chioza et al. (2001) provided evidence that the CACNA1A gene (601011) on chromosome 19p is involved in the etiology of IGE. They analyzed 4 single nucleotide polymorphisms (SNPs) from patients with IGE and found that 1 of them, SNP8, showed significant association with the disease. Because SNP8 is a silent polymorphism, the authors suggested that the association must be with a closely linked variant.
Sander et al. (2000) and Wilkie et al. (2002) reported associations between EIG and a polymorphism in the opioid receptor Mu-1 gene OPRM1 (N40D; 600018.0001). In the study of Sander et al. (2000), the asp40 allele frequency was increased significantly in 72 German patients with IAE (frequency = 0.139) compared to controls (frequency = 0.078; p = 0.019). The authors suggested that a variant OPRM receptor may increase liability to absence seizures, perhaps via modulating other channel currents. Among 230 patients with IGE and 234 controls, Wilkie et al. (2002) found an association for the OPRM1 118G allele with IGE, most often with the GG genotype (a recessive mode of inheritance). However, separate analysis for each IGE subtype showed that there was no association of the G118 allele for a particular subtype, such as those with absence seizures. The paper of Wilkie et al. (2002) was later retracted due to genotyping errors. The corrected results showed no association between EIG and SNPs in the OPRM1 gene.
For discussion of a possible association between adolescent-onset EIG and homozygosity for a 9-SNP haplotype on the ME2 gene, see 154270.0001.
For discussion of a possible association between EIG and variation in the CLCN1 gene, see 118425.0021.
Toth et al. (1995) found that insertional inactivation of the mouse jrk gene resulted in handling-induced whole body jerks, generalized clonic seizures, and epileptic brain activity, a phenotype termed 'jerky.' All homozygous animals displayed seizures. Homozygotes also displayed some degree of kyphosis of the thoracic spine and were proportionate dwarfs. Approximately half died before 3 months of age. Approximately 50% of the hemizygous animals showed generalized clonic seizures. The other hemizygous animals either displayed seizures limited to the head and limbs or showed no seizure activity. There was no apparent correlation between the level of jerky mRNA and the severity of seizures in hemizygotes.
Vadlamudi et al. (2004) reviewed the copious notes of William Lennox, who studied the genetics of epilepsy (Lennox and Lennox, 1960) and first postulated a major genetic influence in idiopathic generalized epilepsies.
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McCorry, D., Nicolson, A., Smith, D., Marson, A., Feltbower, R. G., Chadwick, D. W. An association between type 1 diabetes and idiopathic generalized epilepsy. Ann. Neurol. 59: 204-206, 2006. [PubMed: 16374819] [Full Text: https://doi.org/10.1002/ana.20727]
Moore, T., Hecquet, S., McLellann, A., Ville, D., Grid, D., Picard, F., Moulard, B., Asherson, P., Makoff, A. J., McCormick, D., Nashef, L., Froguel, P., Arzimanoglou, A., LeGuern, E., Bailleul, B. Polymorphism analysis of JRK/JH8, the human homologue of mouse jerky, and description of a rare mutation in a case of CAE evolving to JME. Epilepsy Res. 46: 157-167, 2001. [PubMed: 11463517] [Full Text: https://doi.org/10.1016/s0920-1211(01)00275-3]
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Wilkie, H., Osei-Lah, A., Chioza, B., Nashef, L., McCormick, D., Asherson, P., Makoff, A. J. Association of mu-opioid receptor subunit gene and idiopathic generalized epilepsy. Neurology 59: 724-728, 2002. Note: Retraction: Neurology 64: 579 only, 2005. [PubMed: 12221164] [Full Text: https://doi.org/10.1212/wnl.59.5.724]
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