Epileptic seizures and syndromes in twins: the importance of genetic factors

The role of genetic factors in the occurrence of epilepsy syndromes was studied in twins recruited from the population-based Danish Twin Registry. A total of 34,076 twins were screened for epilepsy. Cases were confirmed and classified by two neurologists according to the classification systems of the International League Against Epilepsy (ILAE). A total of 214 twin pairs with epileptic seizures and 190 pairs with epilepsy were ascertained. Significantly higher concordance rates were found for monozygotic (MZ) compared to dizygotic (DZ) twins for both epileptic seizures (0.56 for MZ and 0.21 for DZ pairs, P<0.001) and for epilepsy (0.49 for MZ and 0.16 for DZ pairs, P<0.001). Concordance rates were also higher for MZ twins compared to DZ twins for both generalized epilepsy (0.65 for MZ and 0.12 for DZ) and for localization-related epilepsy (0.30 for MZ and 0.10 for DZ). In twin pairs where both members had seizures, 83% of MZ and 65% of DZ pairs had the same major epilepsy syndrome. Genetic factors were found to account for 80% of the liability to both epileptic seizures and epilepsy. In conclusion, analysis of this neurologist-verified epilepsy twin data set has confirmed that genetic factors have a substantial impact on the etiology of epileptic seizures as well as on the occurrence of both generalized and partial epilepsies.     

Is benign rolandic epilepsy genetically determined?

Benign rolandic epilepsy (BRE) is considered to be a genetically determined idiopathic partial epilepsy. We studied twins with BRE and compared the concordance with a twin sample of idiopathic generalized epilepsy (IGE). All eight BRE pairs (six monozygous [MZ], two dizygous [DZ]) were discordant. MZ pairwise concordance was 0 (95% confidence interval [CI], 0-0.4) for BRE compared with 0.7 (95% CI, 0.5-0.9) for 26 IGE MZ pairs. Our data suggest that conventional genetic influences in BRE are considerably less than for IGE, and other mechanisms need to be explored.     

A twin study of Tourette syndrome

In 43 pairs of same-sex twins, in which at least one co-twin had Tourette syndrome (TS), 30 pairs were probably monozygotic (MZ) and 13 were probably dizygotic (DZ). Concordances for TS were 53% and 8% for MZ and DZ pairs, respectively. When diagnostic criteria were broadened to include any tics in co-twins, concordance rates were 77% and 23% for MZ and DZ pairs, respectively. These concordances are consistent with genetic etiology. However, the fact that only 53% of MZ twins were fully concordant indicates nongenetic factors affect expression of TS. Presence of tics in discordant co-twins and timing of onset in partially concordant co-twins support an association between TS and tics in families with TS present. The data are inconclusive on whether some MZ twins with discordant co-twins are etiologically different from those who are concordant.     

Dementia of the Alzheimer type: clinical and family study of 22 twin pairs

We studied 22 twin pairs in which one or both twins had dementia of the Alzheimer type (DAT). In four twins, diagnosis was confirmed by autopsy. Seven monozygotic (MZ) pairs were concordant for DAT; 10 MZ pairs were discordant. Two dizygotic (DZ) pairs were concordant for DAT, and 3 DZ pairs were discordant. The current concordance rate was 41% for MZ twins and 40% for DZ twins. The study supports the belief that, etiologically, DAT cannot be entirely accounted for by a single autosomal dominant gene. The data also suggest that in certain genetic circumstances, disease expression may be delayed in females.     

GENETIC FACTORS IN FEBRILE CONVULSIONS An Investigation of 64 Same-Sexed Twin Pairs

The importance of genetic factors in the aetiology of febrile convulsions (FC) has been evaluated from a study of 64 same-sexed twin pairs and their siblings. The twin pairs were selected from a twin population of 1631 normal same-sexed twin pairs. Eight of the 26 monozygotic (MZ) pairs were concordant with respect to FC, while the non-proband of one further MZ pair suffered from petit mal epilepsy. Five of the 37 dizygotic (DZ) pairs were concordant with respect to FC. The pairwise concordance rates for the MZ and DZ series were 0.28 and 0.11 respectively (chi² = 1.82, 0.10 < p < 0.20), while the MZ and DZ proband concordance rates were 0.46 and 0.20 respectively. The MZ pairwise concordance rate of 0.57 was significantly higher than the DZ concordance rate of 0.09 in the 30 female pairs (chi² = 5.77, 0.01 < p < 0.02). The incidence of FC in sibs of the propositi was 14%. The combination of a high risk of FC in the sibs of the propositi and the non-significant difference between the concordance rates in MZ and DZ pairs indicates that FC are caused by factors shared by sibs, but that these factors are to a great extent of a non-genetic nature. However, the separate analysis of the female pairs demonstrates the existence of genetic aetiological factors.     

A twin study of febrile convulsions in the general population

Seven monozygotic (MZ) and six dizygotic (DZ) twin pairs with febrile convulsions (FC) in the general population were studied. The pairwise concordance rate for FC in MZ 85.7% (6/7) was higher than that in DZ 16.7% (1/6). In a discordant MZ pair, the unaffected co-twin was attacked by epileptic seizures later. Between the concordant DZ twins, the clinical symptoms and EEGs differed in quality. According to the ratio of concordance rate in MZ to that in DZ 5.1, a multifactorial mode of inheritance for FC was suspected.     

A Twin Study of Febrile Convulsions in the General Population

Seven monozygotic (MZ) and six dizygotic (DZ) twin pairs with febrile convulsions (FC) in the general population were studied. The pairwise concordance rate for FC in MZ 85.7% (6/7) was higher than that in DZ 16.7% (1/6). In a discordant MZ pair, the unaffected co-twin was attacked by epi leptic seizures later. Between the concordant DZ twins, the clinical symptoms and EEGs differed in quality. According to the ratio of concordance rate in MZ to that in DZ 5.1, a multifactorial mode of inheritance for FC was suspected.     

Genetic and environmental influences on depressive symptoms by age and gender in African American twins

Depression is typically considered relative to individuals and thought to originate from both biological and environmental factors. However, the environmental constraints and insults that African Americans experience likely influence the concordance by age and gender for depression scores among adult African American twins. Monozygotic (MZ) (n = 102) and Dizygotic (DZ) (n = 110) twins, age 25-88 years in the Carolina African American Twin Study of Aging were examined using an 11-item version of the CES-D measure of depressive symptomatology. Those participants with scores above nine were considered depressed. Overall, the MZ pairs had a higher concordance than the DZ pairs implying genetic influence. Both MZ and DZ males had higher concordances than either female zygosity groups. The difference between the concordance rates for MZ and DZ twin pairs was greater in males than females. By age group, the difference between the concordance rates for younger MZ and DZ twin pairs was much larger than for older pairs. The results suggest that, even though African Americans may be at risk for depression due to contextual/environmental factors, genetic influences remain important.     

Migraine without aura: a population-based twin study.

To investigate the importance of genetic and environmental factors to the etiology of migraine without aura and to compare the symptomatology of migraine without aura in monozygotic and dizygotic twins, 2,680 twin pairs were recruited from the population-based Danish Twin Registry. Monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs, where at least one twin had self-reported migraine or self-reported severe headache with accompanying symptoms, were telephone interviewed by a physician. The participation rate in the telephone interview was 90%. The pairwise concordance rate was significantly higher in MZ than in DZ twin pairs (28% vs 18%). The probandwise concordance rate was 40% (95% CI, 33-48%) in MZ and 28% (95% CI, 23-33%) in DZ twin pairs. The pairwise concordance rates for the different pain characteristics and accompanying symptoms were not significantly different in MZ and DZ twin pairs. However, comparing all of the pairwise concordance rates of pain characteristics and accompanying symptoms together, MZ twin pairs were significantly more concordant than DZ twin pairs. Our data demonstrate a significant genetic factor in migraine without aura. The size of this factor is modest and the demonstration of susceptibility genes is predicted to be laborious and difficult.     

Cerebral asymmetry in twins: predictions of the right shift theory

A study of the heritability of lobar brain volumes in twins has introduced a new approach to questions about the genetics of cerebral asymmetry. In addition to the classic comparison between monozygotic (MZ) and dizygotic (DZ) twins, a contrast was made between pairs of two right-handers (RR pairs) and pairs including one or more non-right-hander (non-RR pairs), in the light of the right shift (RS) theory of handedness. This paper explains the predictions of the RS model for pair concordance for genotype, cerebral asymmetry and handedness in healthy MZ and DZ twins. It shows how predictions for cerebral asymmetry vary between RR and non-RR pairs over a range of incidences of left-handedness. Although MZ twins are always concordant for genotype and DZ twins may be discordant, differences for handedness and cerebral asymmetry are expected to be small, consistent with the scarcity of significant effects in the literature. Marked differences between RR and non-RR pairs are predicted at all levels of incidence, the differences slightly larger in MZ than DZ pairs.     

Genetic epidemiology of epilepsy: a twin study

The study explored the genetic susceptibility and prevalence of epilepsy in twins. The data on epilepsy were retrieved from the health records of 199 pairs of twins. Proband concordance rate in monozygotic (MZ) twins was four times more than that in dizygotic (DZ) twins (0.67 vs. 0.17). Three of 15 (20%) affected twin kinships had epileptic first-degree relatives. These findings indicated significant underlying genetic susceptibility to epilepsy with the Holzinger's heritability estimate being 0.45. The prevalence of epilepsy was similar in MZ (45.45), DZ (45.11) twins, and their non-twin siblings (47.60). In the general population from various nationalities, the mean prevalence rate of epilepsy varied from 5 to 17 per 1000. The appreciably higher prevalence rate in twin kinships could be attributed to peculiar development factors associated with the twinning process or the intrauterine environment of mothers having tendencies to bear twins. Of the genetic markers, PTC locus seemed to be associated with the susceptibility to epilepsy. The allele frequency of non-tasters (t) seemed greater in epileptic twin kinships (0.71) than that in the general population (0.53). The frequency of non-tasters was similar in MZ and DZ twins and singletons: 27.3%, 26%, and 27.7% respectively. The PTC data on the general population was based on a sample of 278 individuals.     

Smoking and Parkinson's disease in twins

OBJECTIVE: To test the hypothesis that cigarette smoking protects against the development of PD. BACKGROUND: Smoking has been inversely associated with PD in many studies, but whether this reflects a biologic effect on the underlying disease process or merely confounding or selection bias remains uncertain. METHODS: The authors compared smoking histories in male twin pairs identified from the National Academy of Sciences--National Research Council World War II Veteran Twins Cohort. The amount of cigarettes smoked (in pack-years) was collected until the time of PD onset in the affected twin or until the time of death for the unaffected twin, whichever came first. Differences in pack-years smoked until PD onset and until 10 and 20 years before onset were compared using paired t-tests. Comparisons were made overall and stratified by zygosity and concordance for PD. To assess the role of shared environment, correlation for smoking behaviors was compared between pairs concordant and discordant for PD. RESULTS: Detailed smoking histories were available for 113 twin pairs in which at least one twin had PD (discordant pairs: 43 monozygotic [MZ], 50 dizygotic [DZ]; concordant pairs: 10 MZ, 10 DZ). Within-pair correlation for ever smoking was high in MZ pairs (phi = 0.47, p = 0.001) but not in DZ pairs (phi = 0.007, p = 0.96). In 33 discordant MZ pairs and 39 discordant DZ pairs in which at least one twin had smoked, the twins without PD smoked more than their brothers smoked (32.5 vs. 22.7 pack-years, p = 0.026). This was more marked in the MZ pairs (37.1 vs. 25.3 pack-years, p = 0.077) than in the DZ pairs (28.6 vs. 20.5 pack-years, p = 0.17). A similar relationship was seen when smoking dose was calculated only until 10 years before PD onset, suggesting that the lower dose of smoking in the twin with PD was not the result of early, undiagnosed disease. CONCLUSION: Within twin pairs, risk of PD is inversely correlated with the dose (in pack-years) of cigarette smoking. This effect is most pronounced in MZ twins, despite the high correlation for smoking. Because MZ twins are genetically identical and are similar behaviorally, this difference is unlikely to result from either genetic factors or environmental confounders. These results are compatible with a true biologic protective effect of cigarette smoking.     

Evidence of a genetic factor in migraine with aura: A population-based Danish twin study

We studied the genetic influence on cause of migraine with aura (MA) by analyzing a twin population. The twin sample consisted of 2,026 monozygotic (MZ) twins and 3,334 same-sex dizygotic (DZ) twins, born from 1953 to 1960, from the population-based New Danish Twin Register. A validated questionnaire was used to screen for migraine, the response rate being 87%, and similar among MZ and DZ twins. All twin pairs with at least 1 twin with possible MA were interviewed by a physician experienced in headache diagnoses. The answers from the questionnaire as well as the zygosity of the twins were blinded for the interviewer. A total of 211 twin pairs were identified, of whom 77 pairs were MZ and 134 pairs were DZ. The lifetime prevalence of MA was 7% and with a male-to-female ratio of 1:1.1. The pairwise concordance rates were significantly higher in MZ (34%) than in DZ twin pairs (12%), emphasizing the importance of genetic factors in MA. However, environmental factors are also important, as the pairwise concordance rate was less than 100% in MZ twin pairs. The recurrence risk of MA was 50% in MZ and 21% in DZ twin pairs. In nontwin siblings, the recurrence risk of MA is 27%, which is similar to the recurrence risk in DZ twins. This indicates that MA is not developed due to specific environmental factors shared by the twins. Ann Neurol 1999;45:242–246     

Gene expression analysis in absence epilepsy using a monozygotic twin design

Purpose: To identify genes involved in idiopathic absence epilepsies by analyzing gene expression using a monozygotic (MZ) twin design. Methods: Genome‐wide gene expression in lymphoblastoid cell lines (LCLs) was determined using microarrays derived from five discordant and four concordant MZ twin pairs with idiopathic absence epilepsies and five unaffected MZ twin pairs. Gene expression was analyzed using three strategies: discordant MZ twins were compared as matched pairs, MZ twins concordant for epilepsy were compared to control MZ twins, and a singleton design of affected versus unaffected MZ twin individuals was used irrespective of twin pairing. An overlapping gene list was generated from these analyses. Dysregulation of genes recognized from the microarray experiment was validated using quantitative real time PCR (qRT‐PCR) in the twin sample and in an independent sample of 18 sporadic absence cases and 24 healthy controls. Results: Sixty‐five probe sets were identified from the three combined microarray analysis strategies. Sixteen genes were chosen for validation and nine of these genes confirmed by qRT‐PCR in the twin sample. Differential expression for EGR1 (an immediate early gene) and RCN2 (coding for the calcium‐binding protein Reticulocalbin 2) were reconfirmed by qRT‐PCR in the independent sample. Discussion: Using a unique sample of discordant MZ twins, our study identified genes with altered expression, which suggests novel mechanisms in idiopathic absence epilepsy. Dysregulation of EGR1 and RCN2 is implicated in idiopathic absence epilepsy.     

Genetic and environmental factors in febrile seizures: a Danish population-based twin study

The relative importance of genetic and environmental factors in the etiology of febrile seizures was estimated using a large, unselected population-based twin sample. A total of 34,076 twins (aged 12-41 years), recruited from the Danish Twin Registry, were screened for febrile seizures by questionnaire. Information was obtained from 11,872 complete pairs. Concordance rates, odds ratios and correlations were used to assess the degree of similarity in monozygotic (MZ) and dizygotic (DZ) twins. Model fitting and estimation of heritability (proportion of the population variance attributable to genetic variation) were performed using standard biometrical methods. Significantly higher probandwise concordance rates were found for MZ compared with DZ twins (0.36 and 0.12, P < 0.01). Odds ratios and correlations showed a similar pattern. An etiological model including additive genetic effects and individual-specific environmental factors provided the best fit to the data with a heritability for febrile seizures of 70% (95% CI: 61-77%). The remaining 30% of the variation could be attributed to individual-specific environmental factors. In conclusion, this study has confirmed a major impact of genetic factors in the etiology of febrile seizures. Future studies aimed at identifying the specific genetic factors and environmental exposures involved in determining febrile seizure risk are clearly warranted.     

Familial temporal lobe epilepsy: A common disorder identified in twins

We describe a new syndrome of familial temporal lobe epilepsy in 38 individuals from 13 unrelated white families. The disorder was first identified in 5 concordant monozygotic twin pairs as part of a large-scale twin study of epilepsy. When idiopathic partial epilepsy syndromes were excluded, the 5 pairs accounted for 23% of monozygotic pairs with partial epilepsies, and 38% of monozygotic pairs with partial epilepsy and no known etiology. Seizure onset for twin and nontwin subjects usually occurred during adolescence or early adult life. Seizure types were simple partial seizures with psychic or autonomic symptoms, infrequent complex partial seizures, and rare secondarily generalized seizures. Electroencephalograms revealed sparse focal temporal interictal epileptiform discharges in 22% of subjects. Magnetic resonance images appeared normal. Nine affected family members (24%) had not been diagnosed prior to the study. Pedigree analysis suggested autosomal dominant inheritance with age-dependent penetrance. The estimated segregation ratio was 0.3, indicating an overall penetrance of 60% assuming autosomal dominant inheritance. The mild and often subtle nature of the symptoms in some family members may account for lack of prior recognition of this common familial partial epilepsy. This disorder has similarities to the El mouse, a genetic model of temporal lobe epilepsy with a major gene on mouse chromosome 9, which is homologous with a region on human chromosome 3.     

Familial influences on the clinical characteristics of major depression: a twin study.

We sought in this study to clarify the role that familial factors play in influencing the clinical presentation of major depression (MD). We examined the similarity of the historical and symptomatic features of MD in 176 pairs of female-female monozygotic (MZ) and dizygotic (DZ) twins from a population-based registry, where both members reported a history of MD defined by DSM-III-R criteria. The age at onset and treatment-seeking were significantly correlated in all twin pairs and the correlation in concordant DZ pairs was actually somewhat higher than in concordant MZ twins. The degree of impairment was modestly correlated in all twin pairs with substantially higher correlations in MZ vs DZ twins. No twin resemblance was observed for number of episodes or longest duration of an episode. Twin resemblance for the clinical features of MD was modest, but so was their consistency for the same individual over successive 1-year periods. However, in 5 of the 6 neurovegetative symptoms involving changes in appetite, weight and sleep, MZ twins were significantly correlated and correlations were significantly greater in concordant MZ vs DZ twins. Although the familial factors that cause twin resemblance for the age at onset and treatment seeking appear to be largely environmental, twin resemblance for the degree of impairment and neurovegetative symptoms are probably due largely to genetic factors. Our results suggest that familial factors influence the predisposition to some clinical features of MD.     

Importance of genetic factors in the occurrence of epilepsy syndrome type: a twin study

Although there is strong evidence that genetic factors contribute to risk for epilepsy, their role in the determination of syndrome type is less clear. This study was undertaken to address this question. Information related to epilepsy was obtained from twins included in 455 monozygotic and 868 dizygotic pairs ascertained from population-based twin registries in Denmark, Norway and the United States. Syndrome type was determined based on medical record information and detailed clinical interviews and classified using the International Classification Systems for the Epilepsies and Epileptic Syndromes. Concordance rates were significantly increased in monozygotic versus dizygotic pairs for all major syndrome groups except localization-related cryptogenic epilepsy. Among generalized epilepsies, genetic factors were found to play an important role in the determination of childhood absence, juvenile absence, juvenile myoclonic, and idiopathic generalized epilepsy; and to a lesser degree for epilepsies with grand mal seizures on awakening. Among localization-related epilepsies, genetic factors contributed to risk for localization-related idiopathic and symptomatic syndromes overall, but did not appear to play an important role in determining risk for frontal, occipital or temporal lobe epilepsy. These results suggest that, while genetic factors contribute to risk for major syndrome types, determined when possible, their contribution to risk for localization-related syndrome sub-types, as defined by specific focality, may be modest.     

Parkinson's disease in twins studied with 18F-dopa and positron emission tomography.

We used 18F-dopa PET to examine concordance for dysfunction of the nigrostriatal dopaminergic system in 18 co-twins of patients with Parkinson's disease (PD) and scanned one clinically concordant monozygotic (MZ) twin pair, 17 asymptomatic co-twins (10 MZ, 7 dizygotic [DZ]), and 13 twins with PD (8 MZ, 5 DZ). Mean 18F-dopa uptake of the twins with PD was significantly reduced in putamen to 38% and in caudate to 66% of normal. Mean putamen 18F-dopa uptake for the 17 asymptomatic co-twins was also significantly reduced (86% of normal), as was putamen tracer uptake for the 10 MZ (87% of normal) and seven DZ (83% of normal) asymptomatic co-twin subgroups. Four of 10 MZ and two of seven DZ asymptomatic co-twins had putamen 18F-dopa uptake reduced more than 2 SDs below the normal mean. Three of these four asymptomatic MZ co-twins had tremor on examination at the time of PET and one has now developed PD 2 years later. Our PET findings give concordances for nigral dysfunction of 45% in the MZ pairs and 29% in the DZ pairs at a 2-SD threshold, and 18% in MZ and 0% in DZ pairs at a 3-SD threshold of significance. These data suggest that the concordance for nigral pathology in PD twins may be higher than previously realized and that the presence of an isolated postural or rest tremor may be a phenotypic expression of PD.     

Neurological abnormalities in schizophrenic twins.

BACKGROUND: Neurological abnormalities (NAs) are well recognized in schizophrenia, though their genetic and environmental determinants, and pathophysiological significance, are poorly understood. METHODS: Sixty-three twin pairs, varying in their zygosity and concordance for schizophrenia, and 73 unaffected control twin pairs were examined for total, primary and integrative NAs using the Neurological Evaluation Scale. RESULTS: NAs were increased in probands with schizophrenia compared to nonschizophrenic co-twins and to healthy control twins but there were no significant differences between patients from the concordant and discordant pairs. NAs in the nonpsychotic co-twins from discordant pairs were increased compared to control twins. There were no significant differences in NAs between the nonschizophrenic co-twins from monozygotic (MZ) and dizygotic (DZ) discordant pairs, but the within pair correlations were greater in the MZ compared to DZ pairs. NAs were modified in all groups by pre-morbid schizotypal traits, and in patients by anti-psychotic medication. CONCLUSIONS: NAs in schizophrenia are determined in part by genetic risk for the illness but the presence of premorbid schizotypal traits, and anti-psychotic medication confer additional risk for NAs.