EIG1, INCLUDED
IGE EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 1, INCLUDED
IDIOPATHIC GENERALIZED EPILEPSY
EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, LOCUS ON CHROMOSOME 8, INCLUDED
EIG
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 ... 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 2q22-q23; EIG10 (613060), caused by mutation in the GABRD gene (137163) on 1p36.3; EIG11 (607628), caused by variation in the CLCN2 gene (600570) on 3q36; and EIG12 (614847), caused by mutation in the SLC2A1 gene (138140) on 1p34.
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 ... 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 IGE 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. Greenberg et al. (2005) focused on a locus on chromosome 18 that appeared to be common to all the adolescent-onset IGE syndromes: JME, JAE, and epilepsy with generalized tonic-clonic seizures. The analysis, which used both case-control and family-based association methods, yielded strong evidence that malic enzyme-2 (ME2; 154270) is a gene predisposing to IGE. They showed that when present homozygously, a ME2-centered 9-SNP haplotype (154270.0001) increases risk for IGE (odds ratio 6.1; 95% confidence interval 2.9-12.7) compared with any other genotype examined. Both the linkage analysis and the association analysis supported recessive inheritance for the locus, which is compatible with the fact that ME2 is an enzyme. The study also demonstrated association among subgroups of IGE syndromes.