Neuropediatrics 2006; 37 - CS2_6_1
DOI: 10.1055/s-2006-945556

GENETIC ADVANCES AND DISSECTION OF THE GENERALIZED EPILEPSIES

I Scheffer 1
  • 1The University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Australia

Molecular advances in the genetics of epilepsy have highlighted the key role of ion channel mutations in the pathophysiology of seizure disorders. Both voltage-gated and ligand-gated ion channel subunit mutations are implicated in epilepsy. To date most genes discovered have been for rare epilepsies following monogenic inheritance.

The idiopathic generalized epilepsies (IGE) account for ˜30% epilepsies and are divided into two major subgroups. The classical IGE include Childhood Absence Epilepsy, Juvenile Myoclonic Epilepsy, Juvenile Absence Epilepsy and Generalized Tonic-Clonic Seizures alone. In families where multiple members have classical IGE, family members typically have different phenotypes or subsyndromes. Critical analysis of seizure types shows that syndromes with absence seizures are more likely to segregate in a family whereas myoclonic seizure syndromes segregate in other families.

The second major subgroup is the familial epilepsy syndrome of Generalized Epilepsy with Febrile Seizures Plus (GEFS+). GEFS+ is characterized by phenotypic heterogeneity ranging from febrile seizures and febrile seizures plus, to mild generalized and focal epilepsies, to severe epileptic encephalopathies such as Myoclonic-Astatic Epilepsy of Doose or Severe Myoclonic Epilepsy of Infancy (SMEI). GABAA receptor, sodium, calcium, chloride and potassium channel subunit genes have been implicated in classical IGE and/or GEFS+ phenotypes.

Even in families where a gene of major dominant effect has been identified, syndromic specificity probably relates to several genes interacting possibly with an environmental contribution. In the more common setting of sporadic IGE, epilepsy follows complex inheritance where a number of genes interact to produce a phenotype. Insights into the underlying susceptibility genes, such as calcium channel subunits, are just being gained. Complex inheritance is further complicated by epistatic (gene-gene) and epigenetic effects. Molecular understanding will ultimately enable targeted therapies.