Our evidence for linkage provides the first demonstration of a major genetic effect on susceptibility to idiopathic/cryptogenic localization-related epilepsy. In the current International League Against Epilepsy (ILAE) classification of epilepsy syndromes12
, the term ‘idiopathic’ is reserved for syndromes of presumed genetic origin, and the term ‘cryptogenic’ for syndromes presumed to be nongenetic but with insufficient evidence to assign a specific aetiology. This distinction is not meaningful in the absence of evidence of a clear genetic basis for those defined as ‘idiopathic’ and a clear nongenetic basis for those defined as ‘cryptogenic’. For most of the syndromes currently classified as ‘idiopathic’, clear evidence of a genetic basis, either from linkage studies or demonstration of a specific mode of inheritance, is lacking. In contrast, affected individuals in the family we studied have a form of epilepsy that would be classified as ‘cryptogenic’ according to the ILAE system12
, yet our linkage data provide strong evidence of a genetic susceptibility.
Because of the complexity in the genetic contributions to the epilepsies, clinical syndromes cannot be divided into two broad classes based on a genetic susceptibility. Even in the presence of strong evidence of a genetic contribution to a given syndrome, the susceptibility genotype may be present in only a proportion of those affected, while others have a different genetic mechanism or a nongenetic cause. On the other hand, phenotypic expression may be influenced by other genes or environmental exposures, and thus some of those with a given genotype may manifest a different seizure disorder or epilepsy syndrome. Thus, we believe it more appropriate to use one term (either ‘idiopathic’ or ‘cryptogenic’) to describe cases in whom evidence to establish aetiology is lacking, and to address the question of genetic susceptibility separately.
As affected individuals in this family did not have a recognized ILAE syndrome, we decided a priori to define as affected, for purposes of genetic analysis, anyone in the family who had epilepsy in the absence of a known or suspected exogenous cause. The 11 individuals in the family who met these criteria had similar seizure types and a narrow range of age at onset of epilepsy. This consistency in clinical features is unlikely to result from the effects of modifying genes or shared environmental exposures because the clinical similarity is as great in affected family members who are distantly related and geographically dispersed as in those who are more closely related. Thus the mutation in this family probably influences both susceptibility to epilepsy and its specific clinical features. Although we did not have sufficient data (neuroimaging or depth electrode studies) to localize precisely the epileptogenic abnormality in affected subjects, the auditory features observed in 55% of those affected suggest that the effect of the mutation is localized to a narrowly delimited functional brain region (such as the neocortical temporal lobe).
The human genome database (Welch Library, Johns Hopkins University) lists more than 50 genes whose localization overlaps with the cytological localization (10q22–q24) of the epilepsy susceptibility gene in this family. This list is probably a small fraction of the genes residing in this region, and obviously might not include the gene involved in epilepsy susceptibility in this family. Several previously identified genes are of potential interest, however. There are two neurotransmitter receptors (β-1 and α-2A adrenergic) and several coding sequences with homology to other known receptors. The region contains several genes that are involved in the metabolism of glutamate that could affect the availability of substrates for this important excitatory neurotransmitter. Other genes such as calcium/calmodulin-dependent protein kinase γ may affect epilepsy susceptibility by modulating key metabolic and regulatory pathways. Further evaluation of the relevance of these candidate genes will require more precise localization of both the epilepsy locus on chromosome l0q and the genes themselves.
Because our analysis was restricted to a single family, we cannot estimate the proportion of familial epilepsy that can be attributed to alleles at this locus, which will require the study of additional families. However, even if the mutation found in our family is rare, identification of its product and pathophysiologic effect may help to elucidate basic epileptogenic mechanisms. Study of additional families will also be important for investigating the effects of allelic and locus heterogeneity, and the range of phenotypic manifestations of the susceptibility gene. Linkage to chromosome 10 may be restricted to families with partial epilepsy with auditory features, like that in the family presented here. Even within this type of epilepsy, locus heterogeneity is possible, and some families may not show linkage despite having similar clinical features. On the other hand, alternative alleles at the same locus may raise risk for different types of epilepsy. If this is true, then linkage to chromosome 10 may not be restricted to families with partial epilepsy with auditory features. We are currently investigating these possibilities through linkage analysis in other families.