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.     

The occurrence of epilepsy and febrile seizures in Virginian and Norwegian twins

Twin studies provide an efficient method for examining the importance of genetic and environmental factors in the etiology of disorders such as epilepsy. Population-based twin registries are especially valuable for studies of this type since effects of reporting and self-selection biases on the resulting data are minimized. Among 14,352 twin pairs contained in the Virginia and Norwegian twin panels for whom questionnaire information was available, there was a history of epilepsy in one or both members of 286 pairs; febrile seizures were reported in 257 pairs. Analyses of questionnaire data revealed no significant differences in concordance rates between Virginian and Norwegian twins for either epilepsy or febrile seizures. Probandwise concordance rates for epilepsy were 0.19 in monozygotic twins and 0.07 in dizygotic twins. Analogous rates for febrile seizures were 0.33 (monozygotic) and 0.11 (dizygotic). These results provide further evidence that genetic factors do have a role in the expression of epilepsy and febrile seizures.     

Epilepsy After Febrile Seizures: Twins Suggest Genetic Influence

BackgroundA history of complex febrile seizures can increase the risk of epilepsy, but the role of genetic factors is unclear. This analysis evaluated the relationship between febrile seizures and epilepsy.MethodsInformation on the history of seizures was obtained by a questionnaire from twin pairs in the Mid-Atlantic, Danish, and Norwegian Twin Registries. The information was verified using medical records and detailed clinical and family interviews. The initial study evaluated the genetic epidemiology of febrile seizures in this population. Further information was analyzed and used to evaluate genetic associations of different febrile seizure subtypes.ResultsHistories of febrile seizures were validated in 1051 twins in 900 pairs. The febrile seizure type was classified as simple, complex, or febrile status epilepticus. There were 61% simple, 12% complex, and 7% febrile status epilepticus. There were 78 twins who developed epilepsy. The highest rate of epilepsy (22.2%) occurred in the febrile status epilepticus group. Concordance was highest in simple group.ConclusionA twin with febrile status epilepticus is at the highest risk of developing epilepsy, but simple febrile seizures gave the highest risk for the unaffected twin to develop seizures or other neurological issues. These results are consistent with previous findings. There is a subgroup of febrile seizures that can be associated with long-term consequences. This subgroup can be associated with a significant financial and emotional burden. It is currently not possible to accurately identify which children will develop recurrent febrile seizures, epilepsy, or neuropsychological comorbidities.     

Monozygotic twins with MELAS-like syndrome lacking ragged red fibers and lactacidaemia

Typical cases of MELAS present a combination of clinical and neuroradiological features, lactacidaemia, and ragged red fibers (RRFs) in striated muscle. We have observed a MELAS-like syndrome in monozygotic twins. They developed seizures typically in conjunction with physical exertion, sleep deprivation or febrile episodes. Stroke-like episodes occurred usually during seizures. In twin 2 the course was fatal at age 20 years. Neuroradiological findings were typical of MELAS. Plasma lactate was normal in both. CSF lactate was normal in twin 1 and normal/elevated in twin 2. RRFs were not seen in muscle biopsies of the twins. Complex I activity was reduced in muscle in twin 1. Brain tissue removed at epilepsy surgery in twin 2 showed the presence of mitochondrial angiopathy. The commonest mitochondrial DNA mutation in MELAS, at base pair 3243, was absent. Lactacidaemia and mitochondrial myopathy with RRFs constitute part of the diagnostic criteria of MELAS. However, the absence of these features does not exclude mitochondrial disorder with the serious manifestations of MELAS (seizures and stroke-like episodes) as seen in these twins.     

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.     

Genetic factors in epileptic seizures: evidence from a large twin population

The Finnish Twin Cohort study (27776 individuals; all twins of the same sex born before 1958 and alive in 1967) detected 316 cases of epileptic seizures occurring in 310 twin pairs: 89 monozygotic pairs and 221 dizygotic pairs, including three concordant monozygotic pairs and three concordant dizygotic pairs. The ratio of the observed to expected number of concordant pairs for epileptic seizures was 5.48 (90% CL 1.5–14.2) in monozygotic and 2.12 (90% CL 0.6–5.5) in dizygotic pairs. The results suggest that 8% to 27% of the incidence of epileptic seizures is related to genetic variability. The study of environmental differences in discordant monozygotic pairs should provide insights into the etiology of this group of disorders.     

Status epilepticus in a population-based Virginia twin sample

PURPOSE: To characterize status epilepticus (SE) and estimate its frequency of first occurrence, as well as to assess the contribution of genetic factors to risk of SE occurrence in a sample of Virginia-born twins ascertained from the population-based Mid-Atlantic Twin Registry. METHODS: The occurrence of SE was determined in 13,506 unselected Virginia-born twin pairs ascertained from birth records. Twins included in the study were between ages 2 and 75 years when surveyed. History of seizures and SE was validated through medical records and by detailed personal or parental interviews. RESULTS: Among 381 twins included in 332 pairs with a verified history of seizures, 70 (18.4%) were validated to have had at least one episode of SE. The frequency of first SE in this sample was 309 per 100,000 twins. First SE occurred in conjunction with 21 of 158 febrile and 49 of 223 afebrile seizure cases, respectively. Mean length of SE episode was 76.2 +/- 14.9 min. Age at first SE occurrence ranged from 2 months to 59 years. All concordant twin pairs in the sample were monozygotic (MZ), with a proband-wise concordance rate estimated for SE in this population of 0.31 [95% confidence interval (CI), 0.14-0.52) overall, and 0.67 (95% CI, 0.35-0.90) in pairs concordant for epilepsy. CONCLUSIONS: These results provide a direct estimate of the frequency of SE in a defined population of twins and afford further evidence for a genetic contribution to risk for SE.     

Alzheimer's disease in 22 twin pairs--13-year follow-up: hormonal, infectious and traumatic factors

We obtained follow-up data on 22 sets of twins where at least one twin had Alzheimer's disease (AD). The concordance rate for monozygotic twins (n = 17 pairs) was 59%, whereas that for dizygotic twins was 40%. In our series 8 monozygotic twins had hysterectomies; all had AD. The twins with hysterectomies also had a tendency to develop AD at an earlier age than their co-twin. Five twins with serious systemic infection developed AD, and they tended to have earlier onset than their corresponding twin. We found no strong evidence that head injury predisposed to AD.     

Concordance for multiple sclerosis in Danish twins: an update of a nationwide study

The occurrence of multiple sclerosis (MS) in twins has not previously been studied in complete nationwide data sets. The existence of almost complete MS and twin registries in Denmark ensures that essentially unbiased samples of MS cases among twins can be obtained. In this population-based study, virtually all Danish MS cases among twins born before 1983 with onset of MS after 1948 and diagnosis before I January 1997 were identified. Of 13 286 MS cases, 178 were twins and, of these 164 twin pairs were discordant and seven were concordant. We found significantly higher proband-wise concordance among monozygotic twins than dizygotic twins, with estimated proband-wise concordances of 24% (95% confidence interval (CI): 5-39%) for monozygotic and 3% (95% CI: 0-8%) for dizygotic twins. Thus, a monozygotic twin whose co-twin has MS has a 24% risk of developing the disease, while the corresponding risk for a dizygotic twin is only 3%. Our results largely confirm previously published concordance estimates and indicate that genetic factors are of importance in susceptibility to MS.     

Analyzing the etiology of benign rolandic epilepsy: a multicenter twin collaboration

PURPOSE: Benign rolandic epilepsy (BRE) is considered a genetically determined idiopathic partial epilepsy. We analyzed a large sample of twins from four international twin registers to probe the genetics of BRE. We also aim to synthesize the apparently conflicting family and twin data into a model of BRE etiology. METHODS: Large population-based twin registries of epilepsies from Odense (Denmark), Richmond, Virginia (United States), and Oslo (Norway) were reviewed for BRE cases and added to our Australian twin data. Diagnosis of classic BRE was based on electroclinical criteria with normal neurologic development. Cases with a compatible electroclinical picture but abnormal neurologic development were termed non-classic BRE. RESULTS: Eighteen twin pairs were identified (10 monozygous; eight dizygous) of whom at least one twin was diagnosed with classic BRE among a total sample of 1,952 twin pairs validated for seizures, and all were discordant for BRE. The estimated monozygous pairwise concordance for BRE in this sample was 0.0 [95% confidence interval (CI), 0.0-0.3). Four twin pairs (one monozygous, three dizygous) had non-classic BRE, and all co-twins had seizures. CONCLUSIONS: The twin data showing an absence of any concordant twin pairs with classic BRE suggest that noninherited factors are of major importance in BRE. Modelling the data shows that the familial occurrence of centrotemporal spikes makes only a minor contribution to the familial aggregation of BRE. Genetic factors are probably more important in non-classic BRE. The etiology and mode(s) of inheritance of BRE are much more complicated than initially conceptualized.     

Pattern-reversal visual evoked potentials in normal 7- to 15-year-old twins: a correlation analysis

Pattern-reversal visual evoked potentials (PRVEPs) were tested in 11 sets of monozygotic (MZ) twins and 22 sets of dizygotic (DZ) twins matched on age, sex and educational level. They ranged in age from 7 to 15 years. The PRVEPs of MZ twins exhibited a significantly greater degree of similarity than those of DZ twins. The peak latencies and amplitudes of PRVEP components obtained from MZ twin pairs were significantly correlated. The correlation coefficients for the peak latencies of the P2 (or P100) component were the only ones to differ significantly between the DZ twins of the same sex and DZ twins of opposite sexes. These coefficients, obtained using PRVEPs, were much greater than those obtained with flash visual evoked potentials.     

Epilepsies in twins: Genetics of the major epilepsy syndromes

We studied twins to examine the genetics of epilepsy syndromes. We ascertained 358 twin pairs in whom one or both reported seizures. After evaluation, 253 of 358 (71%) had seizure disorders and 105 pairs were false positives. Among the monozygous (MZ) pairs, more were concordant for seizures (48 of 108; casewise concordance = 0.62 ± 0.05) than among the dizygous (DZ) pairs (14 of 145; casewise concordance = 0.18 ± 0.04). In 94% of concordant MZ pairs, and 71% of concordant DZ pairs, both twins had the same major epilepsy syndrome. When analyzed according to major epilepsy syndrome, the casewise concordances for generalized (MZ = 0.82; DZ = 0.26), both idiopathic (MZ = 0.76; DZ = 0.33) and symptomatic (MZ = 0.83; DZ = 0), were greater than those for partial epilepsies (MZ = 0.36; DZ = 0.05), with intermediate values seen for febrile seizures (MZ = 0.58; DZ = 0.14) an dunclassified epilepsies (MZ = 0.53; DZ = 0.18). We conclude that genetic factors are particularly important in the generalized epilepsies but also play a role in the partial epilepsies. The high frequency of concordant MZ pairs with the same major syndrome strongly suggets there are syndrome-specific genetic determinants rather than a broad genetic predisposition to seizures.     

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.     

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     

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.     

Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism

OBJECTIVE: The broader autism phenotype includes relatives of individuals with autism who display social and language deficits that are qualitatively similar to those of autism but less severe. In previous studies of monozygotic twins discordant for autism, more than 75% of the twins without autism displayed the broader phenotype. Differences in neuroanatomy between discordant monozygotic twins might be associated with the narrow and broader behavioral phenotypes. The authors examined the relationship of twin pair differences in clinical phenotype to differences in neuroanatomic phenotype. METHOD: The subjects were 16 monozygotic twin pairs between the ages of 5 and 14 years and 16 matched singleton comparison subjects. Seven twin pairs were clinically concordant and nine twin pairs were clinically discordant for strictly defined autism. After magnetic resonance imaging, a semiautomated procedure was applied to images in which the brain tissue was subdivided into neurofunctional regions and segmented into gray, white, and ventricular compartments. RESULTS: Both the concordant and discordant twin pairs exhibited concordance in cerebral gray and white matter volumes. However, only the clinically concordant pairs exhibited concordance in cerebellar gray and white matter volumes. Within the discordant twin pairs, both the twins with autism and their co-twins exhibited frontal, temporal, and occipital white matter volumes that were lower than those of the comparison subjects. CONCLUSIONS: These findings support the role and the limits of genetic liability in autism. Continuing to clarify the neuroanatomic pathways in autistic spectrum disorders could illuminate the etiology of autism and, ultimately, contribute to treatments.     

Monozygotic twins discordant for attention-deficit/hyperactivity disorder: ascertainment and clinical characteristics

OBJECTIVE: Nongenetic factors and phenomenology of attention-deficit/hyperactivity disorder (ADHD) were examined in monozygotic (MZ) twin pairs discordant for ADHD. METHOD: Recruitment included telephone screening (n = 297 pairs), behavioral ratings obtained from parents and teachers (n = 59 pairs), and, finally, in-person assessment (n = 25 pairs; structured classroom observation, diagnostic interview, psychoeducational evaluation, birth record review, establishment of monozygosity, and anatomic brain imaging). Affected twins were further contrasted with previously studied affected singletons. RESULTS: Of the 25 MZ twin pairs qualifying for in-person evaluation, only 10 proved discordant for ADHD. Affected twins were mostly comparable with affected singletons on clinical measures, although fathers' self-ratings of childhood ADHD status were significantly lower in twins than in singletons. CONCLUSIONS: Discordance for ADHD in MZ twins appears to be ascribable to greater environmental discordance and decreased familiality. Despite these differences, affected twins were phenotypically comparable with affected singletons. Thus MZ twins discordant for ADHD, while rare, can inform research on the etiology and pathophysiology of this disorder.     

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.     

Suicide in twins

Suicide appears to cluster in families, suggesting that genetic factors may play a role in this behavior. We studied 176 twin pairs in which one or both twins had committed suicide. Seven of the 62 monozygotic twin pairs were concordant for suicide compared with two of the 114 dizygotic twin pairs (11.3% vs 1.8%). The presence of psychiatric disorder in the twins and their families was examined in a subsample of 11 twin pairs, two of whom were concordant for suicide. Eleven of these 13 twin suicide victims had been treated for psychiatric disorder, as had eight of their nine surviving cotwins. In addition, twins in 10 pairs had other first- or second-degree relatives who had been treated for psychiatric disorder. Thus, these twin data suggest that genetic factors related to suicide may largely represent a genetic predisposition for the psychiatric disorders associated with suicide. However, they leave open the question of whether there may be an independent genetic component for suicide.     

Role of genes and environments for explaining Alzheimer disease

CONTEXT: Twin studies using selected samples have shown high heritability for Alzheimer disease (AD). OBJECTIVE: To evaluate genetic and environmental influences on AD in a fully ascertained population of older twins, including like- and unlike-sex pairs. DESIGN: Five-group quantitative genetic model: male monozygotic twins, female monozygotic twins, male dizygotic twins, female dizygotic twins, and unlike-sex twins. SETTING AND PARTICIPANTS: All twins in the Swedish Twin Registry aged 65 years and older. The study included 11,884 twin pairs, among whom were 392 pairs in which 1 or both members had AD. MAIN OUTCOME MEASURES: All individuals were screened for cognitive dysfunction. Suspected cases of dementia and their co-twins received complete clinical diagnostic evaluations for AD. Estimates of heritability, shared environmental influences, and nonshared environmental influences, adjusting for age, were derived from the twin data. RESULTS: Heritability for AD was estimated to be 58% in the full model and 79% in the best-fitting model, with the balance of variation explained by nonshared environmental influences. There were no significant differences between men and women in prevalence or heritability after controlling for age. Within pairs concordant for AD, intrapair difference in age at onset was significantly greater in dizygotic than in monozygotic pairs, suggesting genetic influences on timing of the disease. CONCLUSIONS: In the largest twin study to date, we confirmed that heritability for AD is high and that the same genetic factors are influential for both men and women. However, nongenetic risk factors also play an important role and might be the focus for interventions to reduce disease risk or delay disease onset.