Diagnostic exome sequencing in children: A survey of parental understanding, experience and psychological impact.

Clinical exome sequencing (CES) is increasingly being used as an effective diagnostic tool in the field of pediatric genetics. We sought to evaluate the parental experience, understanding and psychological impact of CES by conducting a survey study of English-speaking parents of children who had diagnostic CES. Parents of 192 unique patients participated. The parent's interpretation of the child's result agreed with the clinician's interpretation in 79% of cases, with more frequent discordance when the clinician's interpretation was uncertain. The majority (79%) reported no regret with the decision to have CES. Most (65%) reported complete satisfaction with the genetic counseling experience, and satisfaction was positively associated with years of genetic counselor (GC) experience. The psychological impact of CES was greatest for parents of children with positive results and for parents with anxiety or depression. The results of this study are important for helping clinicians to prepare families for the possible results and variable psychological impact of CES. The frequency of parental misinterpretation of test results indicates the need for additional clarity in the communication of results. Finally, while the majority of patients were satisfied with their genetic counseling, satisfaction was lower for new GCs, suggesting a need for targeted GC training for genomic testing.

Is there a one-way street from essential tremor to Parkinson's disease? Possible biological ramifications.

There is considerable evidence for an association between essential tremor (ET) and Parkinson's disease (PD), although the topic remains somewhat controversial. An important issue, not previously addressed, is what seems to be the unidirectional nature of the relationship (ET→ET + PD and not PD→PD + ET). The aims of this review are (i) to discuss the evidence for and against a unidirectional relationship and (ii) to discuss the implications of such a unidirectional relationship, if it exists, for disease mechanisms. Evidence 'for' a unidirectional relationship includes (i) abundant clinical anecdotal observation and (ii) clinical and epidemiological studies. Evidence 'against' is theoretical rather than empirical. Overall, the evidence 'for' is stronger, although additional studies are needed in order to be certain; for the time being, it might be best to leave this as an open question. The biological ramifications/extensions of such a unidirectional relationship include (i) that the association is causal (i.e., some aspect of ET pathophysiology predisposes an individual to develop PD) and (ii) that some ET cases may have a circumscribed form of Lewy body disease, and the secondary development of PD may represent a spread of those Lewy bodies in the brainstem. The presence and nature of the links between ET and PD are controversial. Further primary data (epidemiological and pathological) are needed to improve understanding of the relationship and its implications for the pathogenesis of both disorders.

Localization of a gene for partial epilepsy to chromosome 10q.

There is strong evidence for a genetic contribution to epilepsy, but it is commonly assumed that this genetic contribution is limited to 'generalized' epilepsies, and that most forms of 'partial' epilepsy are nongenetic. In a linkage analysis of a single family containing 11 affected individuals, we obtained strong evidence for localization of a gene for partial epilepsy. This susceptibility gene maps to chromosome 10q, with a maximum two-point lod score for D10S192 of 3.99 at theta = 0.0. All affected individuals share a single haplotype for seven tightly linked contiguous markers; the maximum lod score for this haplotype is 4.83 at theta = 0.0. Key recombinants place the susceptibility locus within a 10 centimorgan interval.

Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease.

BACKGROUND: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. METHODS: Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. RESULTS: All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. CONCLUSIONS: Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.

Subclinical tremor in normal controls with versus without a family history of essential tremor: data from the United States and Turkey.

BACKGROUND AND PURPOSE: Mild action tremor is very common in the population. One fundamental question is whether this tremor is related to the neurological disease essential tremor (ET), which occurs in a much smaller segment of the population? ET is often genetic, and variable phenotypic expression is well-documented in the literature. We determined whether normal controls who report a family history of ET have greater action tremor than normal controls who do not report such a history. METHODS: Controls, enrolled in two epidemiological studies (New York and Turkey), were examined in detail and action tremor was rated using a valid and reliable clinical rating scale, resulting in a total tremor score (range 0-36). RESULTS: In New York, the total tremor score was higher in 44/406 (10.8%) controls who reported a family history of ET than in 362/406 controls with no such history (4.25 +/- 2.51 vs. 3.78 +/- 2.93, P = 0.02). Controls who reported a first-degree relative with ET had the highest total tremor scores. In Turkey, the total tremor score was higher in 7/89 (7.9%) controls with a family history than in 82/89 controls with no family history (3.43 +/- 4.54 vs. 1.13 +/- 2.54, P = 0.048). All affected relatives in Turkey were first-degree. CONCLUSIONS: These data suggest that some of the normal tremor exhibited by people in the population is likely to be subclinical, partially expressed ET and that the sphere of ET is wider than is apparent from a consideration of clinically diagnosed cases.

Biomarkers of environmental tobacco smoke in preschool children and their mothers.

BACKGROUND: Adverse health effects attributable to environmental tobacco smoke (ETS) include respiratory illness and lung cancer in nonsmokers. There is accumulating evidence that children may be at heightened risk of cancer later in life as a result of exposure to carcinogens during their early development. It is of concern that as many as 9 million American children under the age of 5 years may be exposed to ETS. PURPOSE: Our goal was to assess whether levels of cotinine and polycyclic aromatic hydrocarbon-albumin (PAH-albumin) are associated with ETS exposure in children and in women of reproductive age, after accounting for background exposures to PAHs in the diet, workplace, and the home environment. METHODS: The study cohort was composed of 87 Hispanic and African-American mothers and 87 of their preschool children (2-5 years of age). Plasma cotinine was analyzed by gas chromatography; PAH-albumin adducts in peripheral blood were analyzed by enzyme-linked immunosorbent assay. Exposure data were obtained by interview-administered questionnaires. RESULTS: Both cotinine and PAH-albumin were significantly higher in the children whose mothers smoked than in the children of nonsmoking mothers (P < .001 and P < .05, respectively). Among the children of nonsmoking mothers, cotinine levels were also significantly higher in those who had ETS exposure from others in the household compared with the unexposed children. By regression analysis, after adjustment for ethnicity, there was a significant dose-response relationship between cotinine and the number of cigarettes smoked per day by the mother, both in the children (partial r2 = .23; P = .01) and in the mothers (partial r2 = .22; P = .01). Among the nonsmoking mothers, regression of biomarkers against total passive smoking exposure also showed a significant association with cotinine (r2 = .25; P = .04). PAH-albumin did not show the same dose-related response with the smoking variables. Mothers' cotinine levels were significantly correlated with those of their children (r = .76; P < .001) as were PAH-albumin adducts (r = .27; P = .014). CONCLUSION: ETS exposure of young children via their mothers' smoking is associated with increases not only in the internal dose of ETS (cotinine), which has been previously reported, but also in the biologically effective dose of the carcinogenic (PAH) components of ETS (PAH-albumin adducts). This observation underscores the carcinogenic and public health hazard of ETS. IMPLICATIONS: Given the relatively low level of ETS exposure in this study, these results reinforce the need for effective programs aimed at smoking prevention and cessation among women, particularly women of reproductive age and minorities.

Family history as an independent risk factor for coronary artery disease.

The risk of family history of ischemic heart disease independent of other well described risk factors has remained difficult to quantitate. Significant coronary artery disease was determined by coronary arteriography to be present in 223 patients and absent in 57 control subjects. Age, sex, blood pressure, serum cholesterol, cigarette smoking and the presence of diabetes and left ventricular hypertrophy on the electrocardiogram were tabulated for each patient and the data used to assign a risk score based on the American Heart Association multivariate model. Subjects were stratified and matched according to risk score to estimate risk of family history independent of familial aggregation of these seven other risk factors. Angina, myocardial infarction, cardiac death and any ischemic heart disease were ascertained in 1,319 first degree relatives. Odds ratios for overall, stratified and matched comparisons of these end points in relatives of patients and control subjects ranged between 2.0 and 3.9 (p less than 0.01 for all comparisons), indicating a higher frequency of all ischemic heart disease end points in relatives of patients with documented coronary artery disease. Life table comparison of patients at lowest risk with those at higher risk showed significantly greater cumulative frequency and earlier age of onset of all ischemic heart disease end points in relatives of low risk patients. These observations indicate that some of the risk associated with family history is independent of familial aggregation of other known risk factors and suggest that the independent effects of family history may be most important in individuals who otherwise are at low risk.

Familial aggregation of Paget's disease of bone.

This epidemiologic study of Paget's disease of bone used data from 788 cases and 387 spouse controls to investigate the following: (1) the extent to which this disorder aggregates in families; (2) the cumulative incidence of the disease in first-degree relatives of patients throughout life; and (3) the influence of age at diagnosis (less than 55 versus 55+ years) and presence of bone deformity in the case on risk of Paget's disease in relatives. A positive family history in parents or siblings was reported by 12.3% of cases and 2.1% of controls. The rate of Paget's disease was approximately seven times as high in relatives of cases as in relatives of controls, and this increased rate did not differ according to gender of case or control or gender of relatives. Cumulative incidence of Paget's disease to age 90 was much higher in relatives of cases (8.9 +/- 1.0% SEM) than in relatives of controls (1.8 +/- 0.9% SEM). Among relatives of cases, cumulative risk was highest when the case had both early age at diagnosis and bone deformity (20.7 +/- 3.6% SEM) compared with risk when the case had early age at diagnosis but not bone deformity (10.8 +/- 3.2% SEM), bone deformity but not early age at diagnosis (5.8 +/- 1.3% SEM), or neither bone deformity nor early age at diagnosis (3.6 +/- 0.8% SEM). Risk in siblings of cases was higher when a parent was affected (22.1 +/- 8.0% SEM) than when both parents were unaffected (6.7 +/- 1.1% SEM).(ABSTRACT TRUNCATED AT 250 WORDS)

Are generalized and localization-related epilepsies genetically distinct?

BACKGROUND: Whether the genetic influences are distinct for generalized and localization-related epilepsies or whether some susceptibility genes raise the risk for both types of epilepsy is uncertain. OBJECTIVE: To evaluate genetic heterogeneity in epilepsy. METHODS: We used Cox proportional hazards analysis to compute rate ratios (RRs) for generalized and localization-related idiopathic or cryptogenic epilepsy in the first-degree relatives of 1498 adult probands with idiopathic or cryptogenic epilepsy ascertained from voluntary organizations. The reference group comprised the first-degree relatives of 362 probands from the same study with postnatal symptomatic epilepsy in whom the genetic contributions appear to be minimal. RESULTS: In the parents and siblings, the risk for all idiopathic or cryptogenic epilepsy was greater if the proband's epilepsy was generalized than if it was localization-related (RR, 4.7 vs 2.4). However, in the parents and siblings of each group of probands, the increased risk was not restricted to the same type of epilepsy as in the proband. The results differed in offspring, with a greater risk for all types of epilepsy if the proband's epilepsy was localization-related than if it was generalized (RR, 4.2 vs 1.6) and a greater risk for localization-related epilepsy than for generalized epilepsy (RR, 7.8 vs 1.8) if the proband's epilepsy was localization-related. CONCLUSIONS: These findings in parents and siblings suggest that some susceptibility genotypes raise the risk for both generalized and localization-related epilepsies but are more common in persons affected with generalized epilepsy. The different findings in offspring may reflect a different influence on susceptibility in that subgroup.

Mild tremor in relatives of patients with essential tremor: what does this tell us about the penetrance of the disease?

BACKGROUND: Mild tremor may occur in relatives of patients with essential tremor (ET). However, this phenomenon has not been studied quantitatively or with a comparison group. Such a study may provide information on the penetrance of ET. OBJECTIVE: To obtain data on the magnitude of tremor in case and control relatives who did not meet diagnostic criteria for ET. METHODS: Cases with ET and control subjects from the Washington Heights-Inwood community in northern Manhattan, NY, were enrolled in a family study. Their first- and second-degree relatives underwent a videotaped tremor examination. Two neurologists rated the severity of tremor, assigning a total tremor score (0-36 [maximum]). Data were analyzed on 201 case relatives and 212 control relatives who did not meet diagnostic criteria for ET. RESULTS: The mean total tremor score of first-degree case relatives was higher than that of first-degree control relatives (4.9 vs 3.9; P<.003). Total tremor scores for second-degree relatives did not differ (4.1 vs 4.2; P =.68). A larger percentage (55.2% vs 36.6%; P =.01) of first-degree case relatives had total tremor scores of 4 or more. Among first-degree relatives who were older than 60 years, 13 case relatives (59.1%) and 18 control relatives (45.0%) had total tremor scores of 4 or more. CONCLUSIONS: A considerable number of seemingly normal case relatives may have a genetic predisposition for tremor. Even among older case relatives (> or =60 years of age), there was an increased prevalence of higher tremor scores, suggesting that in that age group, subclinical ET may be present and penetrance still may not be complete.

Familial aggregation of Alzheimer disease among whites, African Americans, and Caribbean Hispanics in northern Manhattan.

BACKGROUND: Alzheimer disease (AD) aggregates in families. OBJECTIVE: To compare the familial aggregation and lifetime risk of AD to the age of 90 years in the first-degree relatives of patients with AD and unrelated controls among Caribbean Hispanics, African Americans, and whites in Washington Heights, Manhattan, New York, NY. METHODS: Family history of AD and demographic information were obtained from informants of 435 patients with probable or possible AD concerning 1577 siblings and parents and from 1094 controls without dementia concerning 3952 siblings and parents. RESULTS: Lifetime risk of AD to the age of 90 years was 25.9% in relatives of patients and 19.1% in relatives of controls. Rate ratio (RR) for AD in relatives of patients compared with relatives of controls was 1.5 overall (95% confidence interval [CI], 1.2-1.9), and was greater for siblings (RR, 1.8; 95% CI, 1.2-2.5) than for parents (RR, 1.2; 95% CI, 0.9-1.8). Within ethnic groups, RR for AD among relatives was significantly elevated in whites (RR, 2.0; 95% CI, 1.2-3.3) and Hispanics (RR, 1.5; 95% CI, 1.1-2.1), but the difference did not reach statistical significance in African Americans (RR, 1.4; 95% CI, 0.7-2.7). Risk of AD was greater among relatives who were women compared with men (RR, 1.5; 95% CI, 1.2-1.9). CONCLUSIONS: Familial aggregation of AD was increased among families of patients compared with those of controls in all 3 ethnic groups. Risk of AD was highest among siblings and women relatives.

Polycyclic aromatic hydrocarbon-DNA adducts in white blood cells and urinary 1-hydroxypyrene in foundry workers.

In an ongoing comprehensive evaluation of biological markers, workers in or near an iron foundry with varying exposure to polycyclic aromatic hydrocarbons (PAH) were analyzed for molecular response to this exposure. Exposure to benzo(a)pyrene, determined by personal monitors worn by the workers (2 to 60 ng/m3), was considerably lower than in a previous study at this foundry (< 50 to 200 ng/m3) (F.P. Perera et al., Cancer Res., 48: 2288-2291, 1988). Two biomarkers, 1-hydroxypyrene in urine measured by high-performance liquid chromatography with fluorescence detection (a measure of internal dose) and PAH-DNA adducts in WBC measured by immunoassay (a measure of biologically effective dose) were assessed to demonstrate their relationship to the lowest exposures yet analyzed in foundry workers. In addition, these markers were analyzed for dose response and interindividual variability. Cigarette smoking, but not age or charbroiled food, influenced the level of 1-hydroxypyrene but not PAH-DNA adducts. When workers were classified into three exposure categories (low, medium, and high), mean 1-hydroxypyrene levels were 2.7, 1.8, and 3.6 mumol/mol creatinine, respectively. Comparisons by analysis of variance showed a significant difference between the groups after controlling for smoking (P = 0.02), but a trend test using multivariate linear regression analysis was not significant (r = 0.27; P = 0.07). Substantial interindividual variation was demonstrated by the 19- to 20-fold range in the values within each of the three exposure groups.(ABSTRACT TRUNCATED AT 250 WORDS)

CYP1A1 messenger RNA levels in placental tissue as a biomarker of environmental exposure.

The human CYP1A1 gene codes for an inducible enzyme system involved in biotransformation of certain xenobiotics, including polycyclic aromatic hydrocarbons; some of the metabolites are carcinogenic and mutagenic. Effects of environmental exposures (smoking, air pollution, and diet) on CYP1A1 gene induction in placental tissue and the modulation of induction by the CYP1A1 MspI RFLP were evaluated in two groups from Poland: 70 mother-child pairs from Krakow, a city with elevated air pollution; and 90 pairs from Limanowa, a less polluted area. Compared to placentas from nonsmoking women, CYP1A1 mRNA levels were significantly increased in placentas from current smokers (P < 0.001). Ex-smokers also had significantly higher placental mRNA levels, including women who quit smoking prior to pregnancy (P < 0.01). A marginal increase in CYP1A1 mRNA with environmental tobacco smoke exposure was evident. Within Krakow, there was an increase in CYP1A1 mRNA with ambient pollution at the place of residence for each woman, which was significant among women who were not employed away from the home (P < 0.05 controlling for smoking status, diet, and use of coal for heating). Significant increases in mRNA were associated with dietary consumption of smoked meat, cheese, and fish (P < 0.01). The CYP1A1 MspI RFLP was not a significant determinant of CYP1A1 mRNA levels after controlling for smoking and other variables. Human placenta provides a readily available and responsive system that can serve as a model for evaluating environmental and genetic determinants of CYP1A1 induction.

Decline of DNA damage and other biomarkers in peripheral blood following smoking cessation.

Serial samples from 40 heavy smokers ( > or = pack/day for > or = 1 year) enrolled in a smoking cessation program were assayed for cotinine, polycyclic aromatic hydrocarbon (PAH)-DNA, 4-aminobiphenyl-hemoglobin (4-ABP-Hb) adducts, and glycophorin A (GPA) mutations. Blood samples were taken while subjects were smoking, and 10 weeks and 8 and 14 months after quitting. Cotinine was used to assess compliance with the cessation protocol. A significant reduction in mean PAH-DNA and 4-ABP-Hb adducts was observed after cessation in all persons who were cotinine-verified quitters ( < or = 25 ng/ml) for > or = 8 months (P < 0.05). Neither the GPA N/phi nor the GPA N/N mutation Vf was significantly reduced after smoking cessation, but results are limited by the small number (n = 18) of heterozygous individuals studied. The substantial reduction (50-75%) in PAH-DNA and 4-ABP-Hb adduct levels after quitting indicates these carcinogen adducts are reflective of smoking. Passive exposure to smoke at home was significantly associated with PAH-DNA adducts in active smokers and in ex-smokers 10 weeks after quitting (P < 0.01). The estimated half-life of the PAH-DNA adducts in leukocytes is 9-13 weeks by inspection of the mean biomarker levels from baseline and 10 weeks sample and 23 (95% confidence interval, 10-36 weeks) using a linear regression model that adjusted for background.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk of epilepsy in offspring of affected women: association with maternal spontaneous abortion.

BACKGROUND: Previously, the authors found that risk of spontaneous abortion was increased in the pregnancies of women with epilepsy compared with their same-sex siblings, which could have implications for risk of epilepsy in their offspring. An association between a history of spontaneous abortion in the mother and risk of epilepsy in her live-born offspring may arise through selective loss of fetuses with a genetic susceptibility to epilepsy or through intrauterine environmental factors that may predispose the mother to a spontaneous abortion and to epilepsy in her live-born children. METHOD: The authors examined the relation of a history of spontaneous abortion to the risk of idiopathic or cryptogenic epilepsy in 791 live-born offspring of 385 women with cryptogenic localization-related epilepsy (probands) ascertained from voluntary organizations. A semistructured telephone interview with probands and additional family informants, supplemented by medical record review, was used to obtain information on seizures and other risk factors in probands and relatives. RESULTS: Live-born offspring of women with a history of spontaneous abortion were four or five times as likely to develop epilepsy as were children of women without (12.8% versus 4.7%; rate ratio = 4.6, 95% CI: 2.3-9.0). Cumulative incidence of epilepsy was 21.9% in offspring of women with a history of spontaneous abortion and a family history of epilepsy, compared with 4.7% in offspring of women with neither risk factor. CONCLUSIONS: These results suggest that a history of spontaneous abortion is associated with increased risk of epilepsy in live-born offspring and may be a marker for genetic susceptibility for epilepsy in the mother.

How familial is familial tremor? The genetic epidemiology of essential tremor.

Essential tremor (ET) is commonly assumed to be partly genetic. This is due to a seemingly excess aggregation within certain families. There are many families containing more than one member with ET, and some large kindreds with multiple affected individuals. Despite this, the proportion of ET cases with affected family members is not known. Estimates vary from 17 to 100%. Additionally, none of the published studies employed control subjects. Therefore, it is unknown to what extent ET aggregates within families beyond that expected by chance, and the importance of genetic susceptibility in the etiology of ET at the population level has not been established. Additionally, whether or not some clinical subtypes of ET are more likely than others to be influenced by genetic susceptibility is unclear. Some studies suggest that early-onset ET may be familial, although increased awareness and earlier recognition of symptoms is an issue. Although many data support the view that ET susceptibility is inherited in an autosomal dominant manner, most studies are kindreds or service-based studies that might favor selection of families with apparent autosomal dominant modes of inheritance. One community-based study suggested an autosomal dominant mode of inheritance, but this has not been confirmed in studies of more heterogeneous populations. Further understanding of the extent of familial aggregation, extent of genetic heterogeneity, and mode of inheritance is essential for clinical counseling and for further research aimed at localizing and identifying susceptibility genes.

Comorbidity of migraine and epilepsy.

We investigated comorbidity of migraine and epilepsy by using information from structured telephone interviews with 1,948 adult probands with epilepsy and 1,411 of their parents and siblings. Epilepsy was defined as a lifetime history of two or more unprovoked seizures, and migraine as severe headaches with two or more of the following symptoms: unilateral pain, throbbing pain, visual aura, or nausea. Cumulative incidence of migraine to age 40 was 24% in probands with epilepsy, 23% in relatives with epilepsy, and 12% in relatives without epilepsy. Using Cox proportional hazards analysis to control for years at risk and gender, the rate ratio for migraine was 2.4 (95% CI, 2.02 to 2.89) among probands and 2.4 (1.58 to 3.79) among relatives with epilepsy in comparison with relatives without epilepsy. Migraine risk was highest in probands with epilepsy due to head trauma, but it was significantly higher in every subgroup of probands than in unaffected relatives when probands were stratified by seizure type, age at onset, etiology of epilepsy, and history of epilepsy in first-degree relatives. Age-specific incidence of migraine among probands was increased to a greater extent after onset of epilepsy than before, but it was also significantly increased more than 5 years before onset and 1 to 5 years before onset. These results indicate that migraine and epilepsy are strongly associated, independent of seizure type, etiology, age at onset, or family history of epilepsy.

Is the comorbidity of epilepsy and migraine due to a shared genetic susceptibility?

We tested the hypothesis that the comorbidity of migraine and epilepsy results from a shared genetic susceptibility to the two disorders. We used semistructured telephone interviews to collect information on migraine and epilepsy in the families (parents, siblings, and offspring) of 1,967 adult probands with epilepsy. Epilepsy was defined as a lifetime history of two or more unprovoked seizures, and migraine as self-reported severe headaches with two or more of the following symptoms: unilateral pain, throbbing pain, visual aura, or nausea. As a first test of the hypothesis of shared susceptibility, we assessed risk of migraine in relatives of probands with genetic versus nongenetic forms of epilepsy, using two proxy measures of genetic susceptibility-a first-degree family history of epilepsy and idiopathic/cryptogenic (versus postnatal symptomatic) etiology. Neither of these two measures was associated with risk of migraine in relatives. As a second test, we assessed risk of epilepsy in the relatives of probands with versus without migraine. With the exception of one subgroup (sons of female probands), risk of epilepsy in relatives was not associated with the proband's history of migraine. This pattern of results is inconsistent with the hypothesis of a shared genetic susceptibility to migraine and epilepsy.

Validity of family history data on severe headache and migraine.

This study evaluated the validity of family history data on severe headache and migraine obtained from adult probands with epilepsy in a family study of seizure disorders. We compared the probands' reports of severe headaches and migraines in their parents and full siblings with symptom-based diagnoses based on self-reports. Overall sensitivity was 48% for severe headache and 44% for migraine. When we used reports of severe headaches to screen for migraine headaches in the relatives, sensitivity was 56%. These results indicate that severe headache and migraine are underreported in family history interviews with first-degree relatives. To obtain accurate information on headaches in families for clinical practice and genetic research, direct interviews with each relative may be required.

Comorbidity of migraine: the connection between migraine and epilepsy.

Although an association between migraine and epilepsy has long been discussed, it has rarely been studied systematically. According to the evidence from the large epidemiologic study reviewed in this article, individuals with epilepsy are 2.4 times more likely to develop migraine than their relatives without epilepsy. Risk of migraine is elevated in patients with partial-onset and generalized-onset seizures. The comorbidity of migraine and epilepsy may be explained by a state of neuronal hyperexcitability that increases the risk of both disorders. Clinical and EEG features useful in the differential diagnosis of migraine and epilepsy as well as in the diagnosis of both conditions when they occur concurrently are reviewed. When migraine and epilepsy occur together, therapy with agents effective for both conditions should be considered.