Genetics of Epilepsies in Twins
ABSTRACT & COMMENTARY
Source: Berkovic SF, et al. Epilepsies in twins: Genetics of the major epilepsy syndromes. Ann Neurol 1998;43:435-445.
Several large twin studies (tabulated by Berkovic and colleagues) have identified genetic vulnerability for epilepsy by analyses of monozygotic (MZ) or dizygotic (DZ) twins. A number of syndromes, including most febrile seizures and partial seizures, such as absence attacks, have been identified as heavily genetic in origin. Out of the published 1729 twin studies in the literature to date, however, only 47% have been linked to specific patterns of epilepsy by MZ concordance. Such associations were excluded mainly because most previous large series reported their findings before the current classification of the epilepsies was formulated. The present analysis directly evaluates the concordance of several newly identified epilepsies that have strong genetic origins and descriptively identified syndromes. All twins were personally examined by Berkovic et al.
Twin pairs were initially identified by either direct referral to Berkovic and coworkers or various Australian registries and their families or custodians. All of the latter were mailed screening questionnaires. A total of 611 twin pairs were ascertained, but 253 could not be evaluated for practical reasons such as geography and family sensitivities. Another 105 were falsely identified. These subtractions left 253 pairs for full study. Excluded false positives suffered a number of different conditions, including various forms of syncope or a variety of other conditions. The Table lists the major data produced by the 253 twin pairs.
Table
253 twin pairs and 315 individuals with at least one epileptic seizure
| Monozygotic pairs: 108 (27M, 81F) | |
| Dizygotic pairs: 145 (36M, 43F, 66 mixed) | |
| Age: 17 months-68 years, mean 20.6 years | |
| Overall patterns of seizures in 315 subjects: | |
| generalized seizures |
|
| partial seizures |
|
| febrile seizures alone |
|
| special, neonatal, and unclassified |
|
Of the 108 MZ pairs, 48 (44%) were concordant for seizures, whereas, of the 145 DZ pairs, only 14 (10%) were concordant (P < 0.001). Afebrile or febrile seizures had the same relative concordance as the above.
Among the 48 MZ pairs concordant for seizures, 45 had the same epilepsy pattern and three had mixed syndromes. Among the 45, both generalized idiopathic and symptomatic concordance affected 22 twinships, six concordances had non-symptomatic partial seizures, 13 were special (mostly febrile), and four patterns were unclassified. From DZ pairs (n = 162) only 14 (8.6%) were concordant. Ten had the same syndromes (4 general, 1 partial, 4 special, and 1 unclassified) and four had different, mixed syndromes. As the authors emphasize, major inherited components underlie patterns of epilepsy found in monozygotic twins. By contrast, only seldom do similar seizures arise between dizygotic twins.
COMMENTARY
In their discussion, Berkovic and coworkers emphasize that symptomatic generalized seizures represent almost a quarter of all generalized seizures in MZ twin pairs. Admittedly, they indicate that some of these may be linked to other genetic disorders such as tuberous sclerosis. Furthermore, "cryptogenic" seizures such as nocturnal frontal epilepsy and familial temporal lobe epilepsy appeared in MZ twins in this study almost 3/4 with a frequency of idiopathic generalized seizures. Puzzling is the fact that the authors identified no examples of concordant benign rolandic epilepsy in their series although such have been described in the literature.
Based on the results of this carefully conducted and analyzed study of seizure disorders in MZ and DZ twin pairs, Berkovic et al "challenge" the existence of a single broad genetic predisposition as the fault of heritable epilepsy. Rather, their data strongly suggest that different single or multiple gene combinations are responsible for many different but heritable patterns of epilepsy. -fp
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