Sacred disease secrets revealed: the genetics of human epilepsy

Abstract

Neurons throughout the brain suddenly discharging synchronously and recurrently cause primarily generalized seizures. Discharges localized awhile in one part of the brain cause focal-onset seizures. A genetically determined generalized hyperexcitability had been predicted in primarily generalized seizures, but surprisingly the first epilepsy gene discovered, CHRNA4, was in a focal (frontal lobe)-onset syndrome. Another surprise with CHRNA4 was its encoding of an ion channel present throughout the brain. The reason why CHRNA4 causes focal-onset seizures is unknown. Recently, the second focal (temporal lobe)-onset epilepsy gene, LGI1 (unknown function), was discovered. CHRNA4 led the way to mutation identifications in 15 ion channel genes, most causing primarily generalized epilepsies. Potassium channel mutations cause benign familial neonatal convulsions. Sodium channel mutations cause generalized epilepsy with febrile seizures plus or, if more severe, severe myoclonic epilepsy of infancy. Chloride and calcium channel mutations are found in rare families with the common syndromes childhood absence epilepsy and juvenile myoclonic epilepsy (JME). Mutations in the EFHC1 gene (unknown function) occur in other rare JME families, and yet in other families, associations are present between JME (or other generalized epilepsies) and single nucleotide polymorphisms in the BRD2 gene (unknown function) and the malic enzyme 2 (ME2) gene. Hippocrates predicted the genetic nature of the ‘sacred’ disease. Genes underlying the ‘malevolent’ forces seizing 1% of humans have now been revealed. These, however, still account for a mere fraction of the genetic contribution to epilepsy. Exciting years are ahead, in which the genetics of this extremely common, and debilitating, neurological disorder will be solved.