Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2021 Jan 1.
Published in final edited form as: Ann Neurol. 2019 Nov 18;87(1):132–138. doi: 10.1002/ana.25625

The “Maternal Effect” on Epilepsy Risk: Analysis of Familial Epilepsies and Reassessment of Prior Evidence

Colin A Ellis 1, Samuel F Berkovic 2,3, Michael P Epstein 4, Ruth Ottman 5,6; Epi4K Consortium
PMCID: PMC7147955  NIHMSID: NIHMS1577122  PMID: 31637767

Abstract

Objective:

Previous studies have observed that epilepsy risk is higher among offspring of affected women than offspring of affected men. We tested whether this “maternal effect” was present in familial epilepsies, which are enriched for genetic factors that contribute to epilepsy risk.

Methods:

We assessed evidence of a maternal effect in a cohort of families containing ≥3 persons with epilepsy using 3 methods: (1) “downward-looking” analysis, comparing the rate of epilepsy in offspring of affected women versus men; (2) “upward-looking” analysis, comparing the rate of epilepsy among mothers versus fathers of affected individuals; and (3) lineage analysis, comparing the proportion of affected individuals with family history of epilepsy on the maternal versus paternal side.

Results:

Downward-looking analysis revealed no difference in epilepsy rates among offspring of affected mothers versus fathers (prevalence ratio = 1.0, 95% confidence interval [CI] = 0.8–1.2). Upward-looking analysis revealed more affected mothers than affected fathers; this effect was similar for affected and unaffected sibships (odds ratio = 0.8, 95% CI = 0.5–1.2) and was explained by a combination of differential fertility and participation rates. Lineage analysis revealed no significant difference in the likelihood of maternal versus paternal family history of epilepsy.

Interpretation:

We found no evidence of a maternal effect on epilepsy risk in this familial epilepsy cohort. Confounding sex imbalances can create the appearance of a maternal effect in upward-looking analyses and may have impacted prior studies. We discuss possible explanations for the lack of evidence, in familial epilepsies, of the maternal effect observed in population-based studies.

Epilepsy is a disorder with multiple and varied genetic contributions.1 Many previous studies have observed that epilepsy risk is higher among offspring of affected women than offspring of affected men.2–5 Many explanations for this “maternal effect” have been considered, including genetic mechanisms (X-linked inheritance, mitochondrial inheritance, epigenetic parent-of-origin effects), environmental exposures (maternal seizures or antiepileptic drugs during pregnancy), and methodologic biases. However, none of these possible explanations fully accounts for the observed maternal effect in common epilepsies,2,3 and the cause of thisobservation remains unknown.

Evidence of a maternal effect has come from several different types of analysis (Fig 1): (1) comparison of the prevalence of a history of epilepsy in the offspring of women versus offspring of men with epilepsy (ie, “downward-looking” analysis), (2) comparison of the prevalence of a history of epilepsy in the mothers versus fathers of people with epilepsy (“upward-looking”), and (3) analysis of the the proportion of affected individuals with a family history of epilepsy on the maternal versus the paternal side of the pedigree (“lineage analysis”).

FIGURE 1:

FIGURE 1:

Open in a new tab

Methods of observing maternal transmission of epilepsy risk. (A) Downward-looking analysis, comparing the prevalence of a history of epilepsy in offspring of affected women versus men. (B) Upward-looking analysis, comparing the prevalence of a history of epilepsy among mothers versus fathers of affected individuals. (C) Lineage analysis, comparing family history of epilepsy on the maternal side versus the paternal side of the pedigree.

In this study, we analyzed a cohort of familial epilepsies for evidence of a maternal effect, using each of the approaches described above. A familial cohort is particularly useful for this analysis because it provides large sample sizes of affected relatives, in contrast to population-based epidemiologic studies. We also reassessed prior studies that utilized upward-looking analyses, accounting for confounding sex biases that may have influenced their conclusions.

Subjects and Methods

Data Collection

Ascertainment and data collection of the Epi4K familial epilepsy cohort have been described in detail elsewhere.6,7 Briefly, families contained 3 or more relatives with recurrent unprovoked seizures. Known acquired causes of epilepsy were excluded. Ascertainment occurred at 7 centers in North America, Europe, Australia, and New Zealand. Comprehensive phenotypic data were collected about every affected individual through diagnostic interviews and review of medical records, electroencephalograms, and imaging reports. Data were reviewed to ensure consistency of methods across sites and were synthesized by an expert clinician into electroclinical phenotypes. The multigenerational pedigrees obtained during this data collection process were the primary basis of the current analyses.

Families were classified as “generalized” if every affected individual had generalized (or unclassified) epilepsy; as “focal” if every affected individual had focal (or unclassified) epilepsy; as “mixed” if both generalized and focal phenotypes were present in separate individuals or in one person; and as “genetic epilepsy with febrile seizures plus” (GEFS+) if at least one individual was classified as having the FS+ phenotype and at least one other individual had either FS or FS+.6 Because individuals with structural brain lesions or moderate-or-greater intellectual disability were excluded from the study, the generalized families consisted largely of genetic generalized epilepsies and the focal families largely of nonlesional focal epilepsies. A few families in this cohort have been included in previously published familial epilepsy cohorts.4,8

The Epi4K study was approved by the research ethics committee at each participating site, and all subjects provided informed consent to participate. The current analysis used only deidentified data from that study; therefore, separate ethics approval was not required.

Downward-Looking Analysis

This analysis tested the hypothesis that the prevalence of a history of epilepsy was higher in offspring of affected women than in offspring of affected men. For each affected individual in our cohort, we determined the total number of offspring and number of affected offspring. Monozygotic twins were counted as one offspring (n = 6 pairs). There were no discordant monozygotic twin pairs in this cohort. Nuclear families in which both parents had epilepsy (n = 8 parent pairs) were excluded from this analysis

Statistical Analysis.

The prevalence ratio (PR) was calculated for offspring of affected women relative to offspring of affected men. Confidence intervals were calculated using bootstrap resampling procedures to account for possible within-family correlation of observations. The null hypothesis was equal epilepsy prevalence in these 2 groups of offspring (PR = 1). Subgroup analyses were performed for each familial epilepsy type.

Upward-Looking Analysis

This analysis tested the following hypothesis: among the parents of affected individuals, the prevalence of a history of epilepsy in mothers compared to fathers is higher than expected by chance. The unit of analysis was sibships, defined as a group of siblings with the same mother and father. This avoids counting the same parent multiple times if there were multiple affected siblings. Each sibship was classified as affected if one or more of its members had epilepsy, and as unaffected if none of its members had epilepsy. For half-sibships, the shared parent was counted once whereas the unshared parents were each counted separately. The 8 sibships in which both parents were affected were excluded from this analysis.

Statistical Analysis.

We determined the ratio of affected mothers to affected fathers in affected sibships, and compared this to the same ratio in unaffected sibships. Unaffected sibships are an appropriate control group because they reveal the likelihood of observing epilepsy in mothers versus fathers in this cohort due to chance, independent of whether epilepsy is transmitted to offspring. Odds ratios (ORs) and 95% confidence intervals were calculated for the comparison of affected versus unaffected sibships. ORs were used here because the outcome of interest was the odds that an affected parent was female versus male, whereas in the downward-looking analysis prevalence ratios were used because the outcome of interest was the prevalence of epilepsy among sets of offspring. The null hypothesis was that the ratio of affected mothers to affected fathers was the same in affected and unaffected sibships (OR = 1). Subgroup analyses were performed for each familial epilepsy type.

Lineage Analysis

For affected sibships with neither parent affected, we examined the epilepsy histories of second-degree relatives (grandparents and aunts/uncles). If any of these relatives was affected, the sibship was coded as having a family history of epilepsy on the maternal side or the paternal side, depending on the unaffected parent through whom the sibship was related to the affected second-degree relative. Five sibships with affected relatives on both parents’ sides were excluded from this analysis. We tested the hypothesis of more sibships with maternal family history than paternal family history.

Statistical Analysis.

A binomial probability test was used to compare the observed proportion of sibships with maternal versus paternal family histories to the null hypothesis of equal proportions (0.5). Subgroup analyses were not performed due to small sample sizes.

Statistical Analysis

Statistical analyses were performed in the R programming language, using packages Kinship2, FamAgg, Publish, and boot. Specific analyses are described in each subsection above.

Results

Cohort Characteristics

A complete description of this cohort of familial epilepsies has been previously reported.6

The cohort contained 1,120 individuals with epilepsy from 303 families: 117 families with only generalized epilepsy (417 affected individuals), 62 families with only focal epilepsy (220 individuals), 102 mixed families manifesting both generalized and focal epilepsies (387 individuals), and 22 GEFS+ families (96 individuals). Of the pedigrees used in this analysis, 280 of 303 (92%) spanned 3 or more generations. Among people with epilepsy in the cohort, 57% were female.

Downward-Looking Analysis

Among offspring of affected individuals, prevalence of a history of epilepsy did not differ in offspring of affected women compared to offspring of affected men (Fig 2). This was true in the cohort overall and in each familial epilepsy type. There were also no differences among the specific epilepsy syndromes within the generalized or focal families (data not shown). We emphasize that the offspring epilepsy rates observed in this highly selected cohort of familial epilepsies do not reflect offspring risk in the general population.

FIGURE 2:

FIGURE 2:

Open in a new tab

Results of downward-looking analysis, showing prevalence of a history of epilepsy among offspring of affected mothers versus offspring of affected fathers. CI = confidence interval; GEFS+ = genetic epilepsy with febrile seizures plus; PR = prevalence ratio (offspring of affected mothers relative to fathers).

Upward-Looking Analysis

Among affected sibships, we observed more affected mothers than affected fathers (Fig 3). This was true in the cohort overall and in each familial epilepsy type except for GEFS+. Rather than compare these values to a null hypothesis of 50% affected mothers, we used unaffected sibships as a control group. Among unaffected sibships, we also observed more affected mothers than affected fathers. Comparison of affected versus unaffected sibships revealed no statistically significant differences in the odds that an affected parent was the mother versus the father. Results were similar when stratified by specific epilepsy syndromes within generalized and focal families (data not shown).

FIGURE 3:

FIGURE 3:

Open in a new tab

Results of upward-looking analysis, showing prevalence of a history of epilepsy among mothers versus fathers of subjects with epilepsy. CI = confidence interval; F = female; GEFS+ = genetic epilepsy with febrile seizures plus; M = male; OR = odds ratio (affected sibships relative to unaffected sibships).

We next explored possible reasons for the enrichment of affected mothers compared to affected fathers, observed in both affected and unaffected sibships. In our cohort, there were 1.8 times as many affected women who were mothers as affected men who were fathers (255 vs 141). Put another way, if a sibship with an affected parent is chosen at random from this cohort, the odds are 1.8 (or a 64% chance) that the affected parent is the mother, regardless of whether the sibship is affected or unaffected.

This enrichment of affected mothers resulted from a combination of 2 independent sex imbalances. First, there were more affected female than male subjects with epilepsy overall (57% female; female:male [F:M] ratio = 1.3). Second, the likelihood that an affected subject was a parent (ie, had ≥1 offspring) was higher for affected female than for affected male subjects (40% vs 29%, F:M ratio = 1.4). Multiplying these 2 ratios (1.3 × 1.4) yields the observed 1.8-fold enrichment in affected mothers. These observations fully account for the findings of our upward-looking analysis.

Lineage Analysis

Among 474 affected sibships with neither parent affected, 83 had a family history of epilepsy in at least one second-degree relative (grandparent or aunt/uncle). This family history was on the maternal side in 46 and on the paternal side in 37, which was not significantly different from chance (p = 0.38).

Discussion

We did not find evidence of a maternal effect in this familial epilepsy cohort. Downward-looking analysis revealed similar prevalence of a history of epilepsy among offspring of affected mothers compared to offspring of affected fathers. Upward-looking analysis revealed more affected mothers than affected fathers; this effect was similar for affected and unaffected sibships, and was explained by other confounding sex imbalances. Lineage analysis revealed no significant difference in the likelikhood of family history on the maternal versus the paternal side of the pedigrees.

Downward-Looking Analysis

Most previous studies that utilized downward-looking analyses have found higher rates of epilepsy in offspring of affected women than affected men (Supplementary Table 2).3,8–18 In contrast to the upward-looking approach, the discrepancy between our study and prior downward-looking studies is not readily explained by our analysis. We do not refute the observations of those studies, and a true maternal effect may exist in cohorts other than the one studied here, as discussed below.

The strongest evidence for a maternal effect comes from the Rochester Epidemiology Project, a population-based sample of residents of Olmsted County, Minnesota.3,10,13,15 Annegers et al (1976) observed epilepsy in 10 of 351 (2.8%) offspring of affected women and in 0 of 229 (0%) offspring of affected men.13 In a later study of this cohort, Peljto et al (2014) observed epilepsy in 14 of 355 (3.9%) offspring of affected women and 4 of 279 (1.4%) offspring of affected men.10 This maternal effect was present only for offspring of parents with focal epilepsy (7/210 vs 1/152) and not for those with generalized epilepsy (5/82 vs 3/60). Other studies have observed a maternal effect in generalized epilepsies.12 Studies of the Rochester data observed a low epilepsy risk in offspring of affected men, similar to the baseline population risk. However, the numbers of affected offspring in the Rochester studies were small, and the findings warrant confirmation in an independent population-based study. Preliminary analyses of offspring risks from the large Danish population registry are also consistent with a maternal effect (Jakob Christensen, personal communication).

Upward-Looking Analysis

Most prior studies that utilized upward-looking analyses have observed more affected mothers than affected fathers. Several studies have reported a statistically significant difference when compared to a null hypothesis of equal proportions of affected mothers and fathers.4,5,12 However, our results demonstrate that these analyses are affected by 2 important confounders, namely (1) differences in the proportions of women and men in the cohort (here, more women than men) and (2) higher likelihood of parenthood for women than for men with epilepsy. Each of these sex imbalances, if present in a cohort, will affect the ratio of affected mothers to fathers with epilepsy.

We used unaffected sibships as a control group. Other studies have also observed more mothers than fathers with epilepsy among the parents of unaffected control groups,19–21 although the cause of this imbalance has not been demonstrated until now. We suspect that previous studies reporting a maternal effect on the basis of upward-looking analyses were affected by the same biases present in our data. In our own data, the ratio of affected mothers to fathers would have appeared statistically significant in all families and in the subset of generalized families had we tested (incorrectly) against a null hypothesis of equal numbers of mothers and fathers.

Women with epilepsy are more likely to marry and to become parents compared to men with epilepsy (Supplementary Table 3).18,22–27 In our cohort, women with epilepsy were 1.4 times more likely than men to have any offspring, consistent with prior evidence. The imbalance in parenthood rates between women and men with epilepsy must be accounted for in any upward-looking analysis of maternal transmission of epilepsy risk.

On the basis of the 2 confounding sex imbalances (sex ratio and parenthood ratio) identified in our data, we reassessed previous studies that utilized upward-looking analyses (Supplementary Table 4).4,5,8,9,11,12,19,20,28–34 Most studies reported the numbers of female and male subjects, but none reported parenthood rates. Assuming a parenthood ratio of 1.4 based on the evidence presented above, we calculated for each study the expected ratio of affected mothers to affected fathers, similar to the approach of Ottman et al (1985).2 Under the assumptions of this reassessment, none of the previous studies demonstrated a statistically significant increase in affected mothers above the expected value.

Lineage Analysis

Five previous studies have conducted similar analyses.5,12,29–31All have reported that family history of epilepsy more commonly occurred on the maternal side than the paternal side, and this difference was statistically significant in 2 studies.12,30 In our data, there was no difference in the likelihoodof maternal versus paternal family history of epilepsy. This analysis is not subject to the same biases as the upward-looking analysis, because the sex of the affected second-degree relatives is not considered. However, reporting bias is a concern, as mothers may be more likely to provide family histories and to know their own family history better than their partner’s. Several studies have observed more maternal than paternal family histories of epilepsy in unaffected control subjects, consistent with reporting bias.20,21 Our dataset did not allow us to perform lineage analysis on unaffected sibships.

Is a Maternal Effect Confined to Certain Cohorts?

The possible biological and methodological causes of the maternal effect have been extensively discussed, with no single factor fully explaining the observed data.2 Of special interest here is why this effect is not present in our study nor in one previous study of familial epilepsies.8 Are there explanations for a maternal effect present in unselected epilepsy cases but not in families ascertained through multiple affected individuals?

One possibility is that the distribution of causal genetic and nongenetic factors is different in the families analyzed here than in the general population. Our data collection strategy was specifically designed to enrich the sample for genetic causes of epilepsy, whether involving rare variants of large effect or combinations of common variants of smaller effect. If the maternal effect is due to another type of mechanism underlying risk in the general population, this enrichment for genetic causes might have made it more difficult to detect in the families we studied.

“Selective fertility” is another possible explanation for the maternal effect.2,10 If people with genetic forms of epilepsy have reduced fertility compared to people with nongenetic forms of epilepsy, then given that fertility reductions are greater in men than in women with epilepsy, offspring of affected men will come disproportionately from men with nongenetic epilepsies (compared with offspring of affected women), and relatively fewer of their offspring will inherit the disorder. Epilepsies in our familial epilepsy cohort can be presumed to be strongly influenced by genetic factors, and so this selective fertility might be present in the population but not in our cohort. One previous study explicitly tested this hypothesis and found that men with epilepsy who had a family history of epilepsy did not have reduced fertility compared to men without a family history;35 however, additional studies are needed.

Environmental exposures during fetal development, such as maternal seizures or antiepileptic drugs, could lead to increased epilepsy risk in the offspring of affected mothers. These factors might play a larger role in sporadic cases and a smaller role in familial cases where the influence of genetics is stronger. However, these hypotheses have been tested and did not explain the maternal effect in population studies.3,13,15 Antiepileptic drugs did not increase risk in offspring; maternal seizures during pregnancy were associated with increased risk in offspring, but the maternal effect persisted after adjusting for this variable.3

Finally, ascertainment biases are likely to differ across methodologies, and are particularly relevant to studies of multiplex families, which oversample individuals with affected offspring or parents relative to their occur-rence in the general population. If for some reason this oversampling is more pronounced for men than for women, this could cause a maternal effect that is present in the population to be missed in studies of familial epilepsies.

Limitations

We studied a selected cohort of families containing multiple individuals with epilepsy. Such a cohort is useful for analysis of the genetic architecture of familial epilepsies, but this is not an epidemiologic study. In particular, the rates of epilepsy in offspring in these families are greatly inflated: 10 times higher than the risk to offspring of unselected persons with epilepsy.10 Second, our data were based on interviews, supplemented with medical records and additional family informants when possible, but are still subject to the inaccuracies and potential biases of subjects’ reports. Third, data on unaffected individuals were limited, particularly for branches of the pedigrees without any affected individuals, which precluded some analyses.

Conclusions

We did not find evidence of a maternal effect on epilepsy risk in a cohort of familial epilepsies, using 3 different methods of analysis. Imbalances in sex ratio and parenthood ratio can confound upward-looking analyses and may explain the findings of previous studies that utilized this approach. Our data do not refute previous downward-looking analyses in population-based studies. It remains to be determined why the maternal effect seen in those studies is not evident in familial epilepsies. To clarify the reasons for these findings, the most informative analyses would compare, within a single dataset, offspring risks and fertility rates for probands with epilepsy with and without a family history of epilepsy in parents and siblings. Such an analysis would require a population-based dataset that is large enough to yield sufficient power and systematically ascertained, so that selection bias can be avoided.

Supplementary Material

supplementary information

Acknowledgment

The Epi4K family study was supported by an NIH National Institute of Neurological Disorders and Stroke grant (U01NS077367). S.F.B. was supported by a National Health and Medical Research Council program grant (628952). R.O. was supported by NIH grants R01 NS078419 and P50 HG007257. M.P.E. was supported by NIH grant R01 GM117946. C.A.E. was supported by a Ruth L. Kirschstein National Research Service Award institutional research training grant (T32 NS091008).

We thank all individuals, including patients and their families, who participated in the study, as well as the clinicians and research staff at many institutions who contributed to the study.

Footnotes

Additional supporting information can be found in the online version of this article.

Potential Conflicts of Interest

Nothing to report.

References

  • 1.Thomas RH, Berkovic SF. The hidden genetics of epilepsy—a clinically important new paradigm. Nat Rev Neurol 2014;10:283–292. [DOI] [PubMed] [Google Scholar]
  • 2.Ottman R, Hauser WA, Susser M. Genetic and maternal influences on susceptibility to seizures: an analytic review. Am J Epidemiol 1985;122:923–939. [DOI] [PubMed] [Google Scholar]
  • 3.Ottman R, Annegers JF, Hauser WA, Kurland LT. Higher risk of seizures in offspring of mothers than of fathers with epilepsy. Am J Hum Genet 1988;43:257–264. [PMC free article] [PubMed] [Google Scholar]
  • 4.Marini C, Scheffer IE, Crossland KM, et al. Genetic architecture of idiopathic generalized epilepsy: clinical genetic analysis of 55 multiplex families. Epilepsia 2004;45:467–478. [DOI] [PubMed] [Google Scholar]
  • 5.Pal DK, Durner M, Klotz I, et al. Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy. Brain Dev 2006;28: 92–98. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Epi4K Consortium. Phenotypic analysis of 303 multiplex families with common epilepsies. Brain 2017;140:2144–2156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Ellis CA, Churilov L, Epstein MP, et al. Epilepsy in families: age at onset is a familial trait, independent of syndrome. Ann Neurol 2019; 86:91–98. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Afawi Z, Oliver KL, Kivity S, et al. Multiplex families with epilepsy: success of clinical and molecular genetic characterization. Neurology 2016;86:713–722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Janz D, Durner M, Beck-Mannagetta G, Pantazis G. Family studies on the genetics of juvenile myoclonic epilepsy (epilepsy with impulsive petit mal) In: Beck-Mannagetta G, Anderson VE, Doose H,Janz D, eds. Genetics of the epilepsies. Berlin, Germany: Springer, 1986:43–52. [Google Scholar]
  • 10.Peljto AL, Barker-Cummings C, Vasoli VM, et al. Familial risk of epilepsy: a population-based study. Brain 2014;137:795–805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Echeverria MG. Marriage and hereditariness of epileptics. J Ment Sci 1880;26:346–369. [Google Scholar]
  • 12.Tsuboi T, Christian W. On the genetics of the primary generalized epilepsy with sporadic myoclonias of impulsive petit mal type. Humangenetik 1973;19:155–182. [DOI] [PubMed] [Google Scholar]
  • 13.Annegers JF, Hauser WA, Elveback LR, et al. Seizure disorders in offspring of parents with a history of seizures—a maternal-paternal difference? Epilepsia 1976;17:1–9. [DOI] [PubMed] [Google Scholar]
  • 14.Tsuboi T, Endo S. Incidence of seizures and EEG abnormalities among offspring of epileptic patients. Hum Genet 1977;36:173–189. [DOI] [PubMed] [Google Scholar]
  • 15.Annegers JF, Hauser WA, Elveback LR, et al. Congenital malformations and seizure disorders in the offspring of parents with epilepsy. Int J Epidemiol 1978;7:241–247. [DOI] [PubMed] [Google Scholar]
  • 16.Janz D, Beck-Mannagetta G. Epilepsy and neonatal seizures in the offspring of parents with epilepsy In: Anderson VE, Hauser WA, Penry JK, Sing CF, eds. Genetic basis of the epilepsies. New York, NY: Raven Press, 1982:135–143. [Google Scholar]
  • 17.Beck-Mannagetta G, Janz D, Hoffmeister U, et al. Morbidity risk for seizures and epilepsy in offspring of patients with epilepsy In: Beck-Mannagetta G, Anderson VE, Doose H, Janz D, eds. Genetics of the epilepsies. Berlin, Germany: Springer, 1986:119–126. [Google Scholar]
  • 18.Tsuboi T Genetic risks in offspring of epileptic parents In: Beck-Mannagetta G, Anderson VE, Doose H, Janz D, eds. Genetics of the epilepsies. Berlin, Germany: Springer, 1986:111–118. [Google Scholar]
  • 19.Stein C Hereditary factors in epilepsy. Am J Psychiatry 1933;89: 989–1037. [Google Scholar]
  • 20.Metrakos JD, Metrakos K. Genetics of convulsive disorders.I. Introduction, problems, methods and base lines. Neurology 1960; 10:228–240. [Google Scholar]
  • 21.Tsuboi T Genetic analysis of febrile convulsions: twin and family studies In: Beck-Mannagetta G, Anderson VE, Doose H, Janz D, eds. Genetics of the epilepsies. Berlin, Germany: Springer, 1986: 25–33. [Google Scholar]
  • 22.Lindsay J, Ounsted C, Richards P. Long-term outcome in children with temporal lobe seizures. Dev Med Child Neurol 1979;21: 630–636. [DOI] [PubMed] [Google Scholar]
  • 23.Dansky LV, Andermann E, Andermann F. Marriage and fertility in epileptic patients. Epilepsia 1980;21:261–271. [DOI] [PubMed] [Google Scholar]
  • 24.Schupf N, Ottman R. Likelihood of pregnancy in individuals with idiopathic/cryptogenic epilepsy: social and biologic influences. Epilepsia 1994;35:750–756. [DOI] [PubMed] [Google Scholar]
  • 25.Wada K, Iwasa H, Okada M, et al. Marital status of patients with epilepsy with special reference to the influence of epileptic seizures on the patient’s married life. Epilepsia 2004;45(suppl 8):33–36. [DOI] [PubMed] [Google Scholar]
  • 26.Kim MK, Kwon OY, Cho YW, et al. Marital status of people with epilepsy in Korea. Seizure 2010;19:573–579. [DOI] [PubMed] [Google Scholar]
  • 27.Starck C, Nevalainen O, Auvinen A, Eriksson K. Fertility and marital status in adults with childhood onset epilepsy: a population-based cohort study. Epilepsia 2019;60:1438–1444. [DOI] [PubMed] [Google Scholar]
  • 28.Ounsted C The factor of inheritance in convulsive disorders in childhood. Proc R Soc Med 1952;45:865–868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Gerken H, Kiefer R, Doose H, Volzke E. Genetic factors in childhood epilepsy with focal sharp waves. I. Clinical data and familial morbidity for seizures. Neuropediatrie 1977;8:3–9. [DOI] [PubMed] [Google Scholar]
  • 30.Doose H, Gerken H, Hien-Völpel K, Völzke E. Genetics of photosensitive epilepsy. Neuropediatrics 1969;1:56–73. [DOI] [PubMed] [Google Scholar]
  • 31.Doose H, Baier W. Genetic factors in epilepsies with primarily generalized minor seizures. Neuropediatrics 1987;18(suppl 1):1–64. [Google Scholar]
  • 32.Doose H, Neubauer BA. Preponderance of female sex in the transmission of seizure liability in idiopathic generalized epilepsy. Epilepsy Res 2001;43:103–114. [DOI] [PubMed] [Google Scholar]
  • 33.Heredity Clarke H. and crime in epileptic criminals. Brain 1880;2: 491–527. [Google Scholar]
  • 34.Harvald B On the genetic prognosis of epilepsy. Acta Psychiatr Neurol 1951;26:339–357. [DOI] [PubMed] [Google Scholar]
  • 35.Schupf N, Ottman R. Reproduction among individuals with idiopathic/cryptogenic epilepsy: risk factors for reduced fertility in marriage. Epilepsia 1996;37:833–840. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

supplementary information
NIHMS1577122-supplement-supplementary_information.docx (33KB, docx)

RESOURCES