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The epilepsies are a heterogeneous group of disorders with many causes. However, a genetic aetiology may be present in up to 40% of patients, and this proportion is even higher in epilepsy of childhood onset.1
The past decade has seen spectacular advances in our understanding of the genetics of epilepsy at a molecular level, and several comprehensive reviews are available.2 3 It is apparent that epilepsy genes fall into several quite distinct classes including those in which mutations cause abnormal brain development, progressive neurodegeneration, disturbed energy metabolism, or dysfunction of ion channels. The discovery that several idiopathic mendelian epilepsies are caused by mutations in ion channels, including voltage gated potassium and sodium channels, is the most exciting advance because this might provide a clue to the cause of the more common idiopathic familial epilepsies.
In this short review, the focus is on those mendelian childhood epilepsies for which genes have recently been identified, and non-mendelian epilepsies for which mapping data are available.
Classification of genetic epilepsies
It is helpful to categorise genetic epilepsies according to the mechanism of inheritance involved and according to whether they are idiopathic (primary) or symptomatic.
Three major groups can be recognised according to the mechanism of inheritance:
- (1)
- Mendelian epilepsies, in which a single major locus accounts for segregation of the disease trait in a family.
- (2)
- Non-mendelian or “complex” epilepsies, in which the pattern of familial clustering can be accounted for by the interaction of several susceptibility loci together with environmental factors (or by the maternal inheritance pattern of mitochondrial DNA).
- (3)
- Chromosomal disorders, in which a gross cytogenetic abnormality is present.
In the idiopathic (primary) epilepsies, recurrent seizures occur in individuals who are otherwise neurologically and cognitively intact, whereas in symptomatic epilepsies the seizures are usually one component of a complex neurological phenotype and a detectable anatomical or metabolic abnormality is present.
Over 160 mendelian phenotypes include epilepsy as a component of the phenotype. Although numerous, they are individually rare and probably account for no more than 1% of patients. Most are “symptomatic” and associated with major central nervous system abnormalities or recognisable metabolic disturbances. These include such major disorders as tuberous sclerosis, fragile X syndrome, neurofibromatosis, Angelman syndrome, and the …