Genetics of Epilepsy

Inheritance in epilepsy can be categorized according to the mechanism of inheritance: (1) mendelian disorders in which epilepsy forms part of the phenotype; (2) idiopathic epilepsy with mendelian inheritance; (3) epilepsy with complex inheritance; (4) idiopathic epilepsy associated with cytogenetic abnormality. Relatives of individuals with generalized epilepsy have a four-times greater risk of epilepsy than the general population. This risk is about two-times higher than in the general population for relatives of individuals with partial or focal epilepsy. In the majority of cases, the pattern of risk does not fit a simple genetic model (dominant, recessive, etc.), making it difficult to predict which family members will develop epilepsy. Genetic risk factors decrease with age. Specific genes for juvenile myoclonic epilepsy (JME), one of the more common epilepsy syndromes that accounts for 7% of all cases of epilepsy, include: the chloride channel, CLCN2, BRD2, a putative developmental transcription regulator, EFHC1 which interacts with the calcium channel Cav2.3, and ME2 which encodes for the mitochondrial enzyme malic enzyme 2, which is involved in GABA synthesis.18 Mutations associated with progressive myoclonus epilepsy, a syndrome involving more than a dozen different diseases related to epilepsy, have been mapped to chromosome 21. As with the majority of central nervous system (CNS) diseases, epilepsy appears to be a polygenic disorder19 with genetic associations being easier to obtain with familial forms of the disease than those occurring in the general population.

6.11.3.2.1 Neonatal epilepsy syndromes

These familial epilepsies include: benign familial neonatal convulsions (BFNC); generalized epilepsy with febrile seizures plus (GEFS + ), and server myoclonic epilepsy of infancy (SMEI), and have been associated with mutations in ion channel genes. These mutations include voltage-gated sodium channels (SCN1A-chromosome 2q24, SCN2A-chr2q23-q24, SCN1B-chr19q13), voltage-gated potassium channels (KCNQ2-chr20q13.3, KCNQ3-chr8q24) and the GABA-gated receptor gene, GABRG2 chr5q33-q34. There is extensive locus heterogeneity with mutations in different genes causing similar epileptic phenotypes, e.g., GEFS + can be caused by mutations in SCN1A, SCN1B, and GABRG2. Conversely, different mutations in the same gene can cause clinically distinct phenotypes (allelic heterogeneity). Thus different mutations in SCN1A can result in both GEFS + and the more severe SMEI.

6.11.3.2.2 Genetic focal epilepsies

Genetic focal epilepsies are also familial in origin and include: autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE); familial mesial temporal lobe epilepsy (FMTLE); familial lateral temporal lobe epilepsy (FLTLE); and familial partial epilepsy with variable foci (FPEVF).21 For ADNFLE, three loci and two genes for coding for the subunits of the neuronal nicotinic receptor (NNR) have been identified and produce the same phenotype. ENFL1 (chr20q13.2) has four different mutations in the a4 NNR subunit coding gene, CHRNA4. ENFL2 (chr15q24) is an unknown gene while ENFL3 is associated with mutations in the NNR b2 subunit gene, CHRNB2. For FLTLE, mutations in the LGI1 (leucine rich glioma-inactivated, epitempin) gene, which codes for a membrane protein of unknown function, have been reported.18 For the remainder of the familial genetic focal epilepsies, either none, or multiple (and as yet unresolved) genetic foci have been reported.

6.11.3.2.3 Cavernous angiomas or malformations

Cavernous angiomas or malformations (CMs) are collections of large, closely clustered blood vessels separated from each other by a single layer of endothelium; they are weak and prone to leak blood or hemorrhage, and are inherited in an autosomal dominant manner. Cerebral CMs (CCMs) cause epilepsy in 50-85% of symptomatic patients. Three CCM loci (CCM1, CCM2, and CCM3) have been mapped to chr7q21-q22, chr7p13-p15 and chr3q25.2-q27, respectively.

6.11.3.2.4 Familial febrile convulsions

Familial febrile convulsions (FCs) have a significant genetic component, the presence of which results in a threefold greater risk for experiencing FCs. Genes for the loci FEB1 (chr8q); FEB2 (chr19p) have not yet been identified. FEB3 (chr19q) has been identified in GEFS + and is a mutation in the voltage-gated sodium channel b1 subunit gene, SCN1B.19'22 Studies on the genetics of epilepsy in increasing numbers of patient cohorts has begun to establish that

''there is no discrete biological boundary delineating what were once considered distinct clinical entities. Instead, mutations in ion channels appear to be able to produce an essentially continuous range of phenotypes from the mild to the severe end of the spectrum''20

is a comment that applies to CNS diseases in general. Additionally, these familial associations indicate that the same epileptic phenotype can be produced by mutations in different ion channel genes and that a single mutation can produce different phenotypes, the latter no doubt a reflection of epigenetic causality factors.

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