Clinical investigation of genetic contributions to childhood-onset epilepsies and epileptic syndromes

Although there have been major advances in the understanding of the molecular bases of certain inherited epilepsy syndromes, clinical studies are still needed to verify the possible genetic contributions to common epilepsies. We examined the proportions of positive family histories of epilepsy (within second-degree relatives) and consanguinity (within first-degree relatives) in 311 probands with childhood-onset epilepsy, and found that they had high family history rates of epilepsy (19.3%) and consanguinity (6.1%). A positive family history of epilepsy was found more in probands with generalized epilepsy than in ones with localization-related epilepsy, and more in probands with idiopathic/cryptogenic epilepsy than in ones with symptomatic epilepsy. However, on analysis after the symptomatic epilepsies had been divided into two categories, probands with pre- or perinatal symptomatic generalized epilepsy and ones with postnatal symptomatic localization-related epilepsy showed high positive family history rates, similar to ones with idiopathic/cryptogenic epilepsy. On the other hand, a positive family history of consanguinity was noted more in probands with generalized epilepsy than in ones with localization-related epilepsy, but there was no significant difference between probands with idiopathic/cryptogenic epilepsy and ones with symptomatic epilepsy. These findings suggest that in addition to the hereditary effect on idiopathic/cryptogenic epilepsy, a genetic susceptibility may contribute to the development of pre- or perinatal symptomatic generalized epilepsy, and to that of postnatal symptomatic localization-related epilepsy. Furthermore, a genetic predisposition seems to have an influence through consanguinity on the etiologies of both idiopathic/cryptogenic and symptomatic generalized epilepsies.     

Seizures among families of Indian probands with different epileptic syndromes

OBJECTIVES: To investigate the contribution of hereditary factors in the causation of different epilepsy syndromes. MATERIAL AND METHODS: Occurrence of seizures among first- and second-degree relatives of 5628 Indian probands with epilepsy, and 3357 probands with non-epilepsy neurological disorders (who acted as control population) was documented. Syndromic concordance between epilepsy probands and affected relatives was investigated. RESULTS: Twenty percent epilepsy probands (1129) had affected relatives. Relatives of epilepsy probands were more often affected compared with relatives of non-epilepsy probands (OR: 3.4). Probands with some epilepsy syndromes more often had a positive family history. Relatives of younger probands were at greater risk of having epilepsy. Sibs were more often affected compared with other first- and second-degree relatives (OR: 1.3 and 4.6). Sibs having generalized epilepsies and syndromes and febrile convulsions (FC) were at greater odds of syndromic concordance with probands compared with second-degree relatives. Sibs and second-degree relatives having idiopathic/cryptogenic epilepsy had greater odds for concordance compared with those with symptomatic epilepsies. CONCLUSIONS: One-fifth of probands with all types of epileptic syndromes have family history of seizures. Familial risk of epilepsy correlated with the epilepsy syndrome among probands and their age at presentation. Risk of relatives being affected varied as a function of the relation with probands. Concordance of epilepsy syndromes varied both as a function of the epilepsy syndrome and relation with the probands.     

Clinical Indicators of Genetic Susceptibility to Epilepsy

Summary: We evaluated clinical indicators of genetic susceptibility to epilepsy in the families of 1,957 adults with epilepsy (probands) ascertained from voluntary organizations. Very few of the probands in this series had idiopathic epilepsy syndromes. Among relatives of probands with postnatal CNS insults, risks of epilepsy were no higher than in the general population. Risk was increased in relatives of probands without identified CNS insults (i.e., those with idiopathic/cryptogenic epilepsy) or with neurological deficit presumed present at birth, compared with relatives of probands with postnatal CNS insults. Among relatives of probands with idiopathic/cryptogenic epilepsy, risks were higher in parents and siblings, but not in offspring, of probands with generalized onset as compared with partial onset seizures. Risks in offspring were higher if the probands had onset of idiopathic/cryptogenic epilepsy before age 10 as compared with age 10 years, but risks in parents and siblings were not associated with the proband's age at onset. These results suggest that genetic susceptibility increases risk of some forms of cryptogenic epilepsy and of epilepsy associated with neurological deficit presumed present at birth, but not of postnatal symptomatic epilepsy. The influences on risk in offspring may differ from those in parents and siblings.     

Relations of genetic and environmental factors in the etiology of epilepsy

We assessed the relations of genetic and environmental factors in the etiology of epilepsy. The study population comprised 9,705 first-degree relatives of 1,951 adults with epilepsy ascertained from voluntary organizations. We calculated standardized morbidity ratios for specific etiologies of epilepsy in the relatives of probands with the same etiologies, using population incidence rates from Rochester, MN, as the reference. Relatives of probands with idiopathic/cryptogenic epilepsy had increased risk for idiopathic/cryptogenic epilepsy and for epilepsy associated with neurological deficit presumed present at birth (cerebral palsy or mental retardation) but not for symptomatic epilepsy associated with postnatal central nervous system insults. Relatives of probands with neurodeficits had increased risks for idiopathic/ cryptogenic epilepsy. Risk for epilepsy was not increased among relatives of probands with postnatal symptomatic epilepsy. The degree of increased risk of idiopathic/cryptogenic epilepsy in relatives of probands with idiopathiclcryptogenic epilepsy diminished with increasing age of the relatives; risk was not increased at age 35 or older. These findings support the possibility of a shared genetic susceptibility to epilepsy and cerebral palsy, and suggest that the genetic contributions to postnatal symptomatic epilepsy are minimal.     

Occurrence of Epilepsies in Family Members of Indian Probands with Different Epileptic Syndromes

Summary: Purpose : Large numbers of families with many members having seizures have been used to understand the role of hereditary factors in the pathogenesis of human epileptic syndromes. We aimed to establish a genetic database to form a hypothesis on the possible genetic contributions in different epileptic syndromes.
Methods : The occurrence and patterns of different epilepsies and epileptic syndromes in 1,219 Indian probands and their relatives were studied. The concordance of epilepsies between probands and relatives was also analyzed.
Results : Of probands, 231 (19% of 1219) had first– or second- degree relatives affected with seizures. Incidence of family history in probands with generalized epilepsies (GES) and syndrome of single, small, enhancing lesions (SSEL) was comparable and significantly higher than that in probands with localization-related epilepsies (LRES). The ratio of affected first- to second-degree relatives was close to 4:1. Generalized epilepsies were the commonest type of epileptic syndromes seen among all relatives. The proportion of sibs and second-degree relatives with epileptic syndromes similar to probands was significantly greater in the GES group as compared with the concordant relatives of probands with LRES and SSEL.
Conclusions : A significant percentage of first- and second–degree relatives of probands with all types of epileptic syndromes have seizures. The risk of relatives being affected varied as a function of the relation with the proband. Concordance of epileptic syndromes between probands and relatives was related to the epileptic syndromes in probands. The syndrome of SSEL is probably a benign epileptic syndrome seen in Indians genetically predisposed to seizures. Hereditary factors may play an almost equal role in the predisposition of relatives to epilepsy in families of probands with different epileptic syndromes.     

Clinical genetic studies in benign childhood epilepsy with centrotemporal spikes

Purpose: To accurately determine the frequency and nature of the family history of seizures in patients with benign childhood epilepsy with centrotemporal spikes (BECTS). Method: Participants with BECTS were recruited from the electroencephalography (EEG) laboratories of three pediatric centers and by referral. Pedigrees were constructed for up to three degrees of relatedness for each proband. All available affected and unaffected individuals underwent phenotyping using a validated seizure questionnaire. The proportion of affected relatives according to degree of relatedness was calculated and phenotypic patterns were analyzed. Key Findings: Fifty‐three probands with BECTS had a mean age of seizure onset at 7.8 years (range 2–12 years). Thirty‐four (64%) of 53 patients were male. For 51 participants, pedigrees were available for three degrees of relatedness. Fifty‐seven (2.7%) of 2,085 relatives had a history of seizures: Twenty‐one (9.8%) of 214 first‐degree, 15 (3%) of 494 second‐degree, and 21 (1.5%) of 1,377 third‐degree relatives. Febrile seizures were the most frequent phenotype, occurring in 26 of 57 affected relatives. There were 34 relatives with epilepsy: 6.5% (14 of 214) first‐degree, 1.8% (9 of 494) second‐degree, and 0.8% (11 of 1,377) third‐degree relatives. Of 21 affected first‐degree relatives: 8 of 21 had febrile seizures (FS), 4 had BECTS, 2 had epilepsy‐aphasia spectrum disorder, one had temporal lobe epilepsy with hippocampal sclerosis, 2 had focal epilepsy of unknown cause, 2 had genetic generalized epilepsies, and 3 had miscellaneous. Significance: The frequency of epilepsies in relatives and the heterogeneous syndromes observed suggest that BECTS has a genetic component consistent with complex inheritance. Focal epilepsies are the most common seizure disorder observed in relatives, especially BECTS and epilepsy‐aphasia spectrum disorder. Additional acquired or environmental factors are likely to be necessary for expression of the seizure disorder.     

Postoperative multichannel magnetoencephalography in patients with recurrent seizures after epilepsy surgery

Objectives - Juvenile myoclonic epilepsy (JME) is a common, age related, idiopathic generalized epileptic syndrome. We aimed to define the expression of JME in Indian probands and study the occurrence of seizures/ epileptic syndromes in their family members. Methods - We studied 225 JME probands with a uniform protocol, recording the type and frequency of seizures, precipitating factors, EEG data, and family history. Detailed family pedigrees were drawn to include all the 1st- and 2nd-degree relatives of probands. The seizures/epileptic syndromes in relatives examined were classified in a uniform way. Results - The clinical and EEG characteristics of 225 JME probands from India were similar to those reported in probands from different ethnic backgrounds. The incidence of febrile convulsions in probands with JME was similar to that of the general population but was much lower (0.2%) among their relatives. A positive family history of seizures among 1st- or 2nd-degree relatives was noted in 79 of 225 (35%) probands. The risk of relatives being affected as well as their risk of expressing a type of idiopathic generalized epilepsy (IGE) varied as a function of the degree of relation with the probands. Conclusions - The clinical expression of JME among probands from India is fairly similar to that reported in probands of different ethnic backgrounds. The risk of relatives being affected as well as their risk of expressing a type of IGE (including JME) varies as a function of the degree of relation with the probands. The reduced occurrence of febrile convulsions among the relatives of JME probands probably represents an ascertainment bias. A much larger database of this type should be helpful in understanding the interactions of different genes that are believed to be responsible for some of the inherited human epileptic syndromes like JME and other IGEs.     

Genetic liability to epilepsy in Kerala State, India

BACKGROUND: Familial clustering is common in epilepsies, but pedigree patterns suggest a multi-factorial inheritance. Genetic liability for multi-factorial inheritance is population specific and such data are not available for the population of Kerala or other states in south India. OBJECTIVES: In this study, we have attempted to determine the genetic liability to epilepsy based on an adult population of this state. MATERIAL AND METHODS: Pedigrees were recorded for probands who reported to the Kerala Registry of Epilepsy and Pregnancy. In order to obtain a genetically matched sample for comparison and estimation of empiric risks, we have used the family history of the spouse except when the spouse was proband's relative. The ILAE criteria were followed for diagnosis and classification of epilepsy. RESULTS: Data were collected on 18,419 family members of 505 probands with epilepsy (82 men and 423 women) and 10,231 family members of spouses (control). The frequency of epilepsy in first and second-degree relatives of the spouses was comparable to the population frequency (0.5%), justifying the use of this sample as control. Positive family history was observed in 22.2% of probands and 8.24% of controls (Odd's Ratio 3.2, 95% Confidence Interval 2.12-4.73). An affected first-degree relative was observed in 7.5% of probands. The corresponding figure for GE, LRE and other epileptic syndromes were 10.2%, 5.8% and 5.12%, respectively. The segregation ratio for Juvenile Myoclonic Epilepsy (JME) (1:19) was higher than that for other types of Generalized Epilepsy (GE) (1:24) and Localization Related Epilepsy (LRE) (1:52). Prevalence of epilepsy among the first-degree relatives (1.96%) was greater than the square root of the population frequency (0.51%) and was higher than that for second-degree (1.24%) and third-degree (0.64%) relatives for the probands. Probands had higher parental consanguinity (13.07%) compared to controls (6.64%). The above factors support a complex inheritance. Genetic liability to epilepsy (heritability) is greater for GE (0.6) and significantly higher for JME (0.7) compared to LRE (0.4). A limitation of this study is that the inferences are based on a predominantly adult female proband sample but no gender specific differences were identified. CONCLUSIONS: The observations of this study indicate complex inheritance and the liability values are useful for genetic counseling in the local population. Further studies involving more individuals from younger age group and male gender are envisaged.     

Classification of epilepsy syndromes and role of genetic factors

In this report the types of epilepsy syndromes seen in children in a tertiary referral center in Beirut, Lebanon were studied and the importance of consanguinity and family history in the occurrence of these syndromes was investigated. Records of 230 pediatric patients evaluated during a 1-year period with the diagnosis of single seizure, febrile seizure, or epilepsy were reviewed. Each patient was classified according to the International League Against Epilepsy classification. The occurrence of consanguinity, of family history of febrile seizures or epilepsy, and of other variables was noted. Thirty-six percent of patients were diagnosed with localization-related epilepsy, 21.7% with generalized epilepsy, 11.7% with undetermined generalized or focal, and 24.3% with special syndromes. Twelve percent of patients were diagnosed with idiopathic, 15.1% with symptomatic, and 30.3% with cryptogenic epilepsies. Consanguinity was more common in patients with symptomatic and cryptogenic epilepsies than in patients with idiopathic epilepsies or with incidental seizures (P < 0.05). Family history of epilepsy was more common in patients with symptomatic, cryptogenic, and idiopathic epilepsies than in patients with incidental seizures (P < 0.05). Family history of febrile seizures but not consanguinity was more common in patients with febrile seizures (P < 0.05). We conclude that genetic factors are important not only in idiopathic epilepsies and febrile seizures but also in cryptogenic and symptomatic epilepsies.     

Clinical genetic study in juvenile myoclonic epilepsy

PurposeTo evaluate clinical features of probands with juvenile myoclonic epilepsy (JME) and affected members of their families in order to study clinical genetics of JME.MethodThirteen unrelated families with at least two members with history of seizures were identified; clinical and genealogic data were collected from JME probands and family members.ResultsAll probands had myoclonic and generalized tonic–clonic seizures (GTCS), while absences occurred in 25% of them. The average age of seizure onset was 13 years. Totally 22 members from 13 families had history of seizures with average age of seizure onset at 18 years. Ten family members had JME, three had epilepsy with GTCS, two had juvenile absence epilepsy, one had adult onset myoclonic epilepsy and six of the affected individuals had unclassified type of epilepsy. In five families, JME was the solely clinical feature. JME dominated among siblings, while phenotypic heterogeneity was observed in second and third degree relatives. In three multi-generation families, members with adult onset genetic generalized epilepsies (GGE) were identified.ConclusionWe found phenotypic heterogeneity regarding epilepsy type and age of seizure onset. Using pedigree analysis, we found no evidence for preferential maternal or any other distinctive inheritance pattern. Further study is needed to confirm and clarify the results.     

Idiopathic generalized epilepsies with pure grand mal: clinical data and genetics

OBJECTIVE: To analyze the clinical features and family history of patients with idiopathic generalized epilepsy (IGE), with pure grand mal (GM), divided into epilepsies with GM occurring exclusively on awakening (GMA) and random GM (RGM). METHODS: We studied retrospectively 98 patients from a large epilepsy outpatient clinic. All patients had a full clinical examination and computed cerebral tomography scans (CCT) or magnetic resonance imaging (MRI) when feasible. We analyzed seizure type, seizure frequency, provocative factors, prognosis, electroencephalography (EEG) findings and family history. RESULTS: Sixty-eight patients had GMA and 30 had RGM. The mean age at seizure onset was 16.6 years (+/-6.3 S.D., range: 5-41) and 16.7 years in those with RGM (+/-7.5 S.D., range: 4-42, NSD). Patients with GMA had a longer course of active epilepsy (median 8.5 years) compared to RGM (median 2 years). Seizure-provoking factors, especially sleep deprivation, were significantly (P=0.001) more common in patients with GMA (52/68, 77%) than in the group with RGM (13/30, 43%). Of all patients, 23% (23/98) reported first degree relatives with seizures or epilepsy. Pure GM was found in 41% (12/29) of affected first degree relatives, other idiopathic generalized epilepsy syndromes were less frequently observed (4/29, 14%). The concordance rate was high within the syndrome - none of the patients with RGM had an affected relative with GMA and vice versa only two of affected relatives of GMA patients had RGM. CONCLUSION: GMA seems to be associated with a longer duration of active epilepsy, a higher relapse rate and a stronger tendency to be precipitated by seizure provoking factors. The different concordance rates between the syndromes suggest a genetically different background.     

One-Year Mortality in Bordeaux Cohort: The Value of Syndrome Classification

Summary:  Purpose: To evaluate the usefulness of the International Classification of Epilepsy Syndromes for 1-year mortality in a prospective incidence study of first epileptic seizures.
Methods: Date and cause of death from the treating physician in an incidence study of first afebrile seizures collected 15 years ago in Southwest France. Cases were classified by epilepsy syndrome. A total of 804 patients were included: acute symptomatic (n = 277), unprovoked (n = 439), or unclassifiable (n = 88).
Results: One hundred and fifty-one patients died within the first year: none with idiopathic partial or generalized epilepsy, 16/104 with symptomatic (standardized mortality ratio (SMR) 6.4, 95% CI 3.6–10.3), 1/59 with cryptogenic (SMR 1.7, 95% CI 0.1–9.7 CI) partial epilepsy, 1/14 (SMR 28.1, 95% CI 0.4–156.6) with symptomatic/cryptogenic generalized epilepsy, 2/23 with undetermined epilepsy, 1/135 with isolated seizure (SMR 0.6, 95% CI 0.1–3.1), and 90/277 (SMR 10.3, 95% CI 8.3–12.7) with acute symptomatic seizures. Unclassifiable seizures could not be classified as acute symptomatic or unprovoked: associated with alcohol abuse (death: 3/32, SMR 7.7, 95% CI 1.6–22.6), brain tumors (death: 31/39, SMR 41.5, 95% CI 28.2–58.9), and dementia (death: 6/17, SMR 5.4, 95% CI 2.0–11.7). Most deaths were due to progression of underlying disease, only 5.9% were seizure-related.
Conclusions: Although a syndromic diagnosis is important for treatment decisions and some prognostic aspects of seizure disorders, its value in mortality studies is limited. Mortality can be calculated only at the first (partial, generalized, and undetermined epilepsies, and special syndromes) and the second (idiopathic vs. symptomatic or cryptogenic) levels of the International Classification of Epilepsies.     

Has familial aggregation in Alzheimer's disease been overestimated?

Studies of the familial aggregation of Alzheimer's disease have primarily used samples ascertained from tertiary care clinics which may not be representative of many AD patients, for example those residing at geriatric nursing homes. Survival analysis was used to investigate whether estimates of familial aggregation of AD based on a clinic-based AD proband (C-AD) sample (probands: N=544; first degree relatives; N=4267) differ from one ascertained at a nursing home (NH-AD; probands: N=225; first degree relatives; N=1772). The cumulative survival from AD was significantly worse in relatives of the C-AD probands and the overall relative risk (RR) of AD in this group was greater than twice that of relatives of the NH-AD probands. However, age at onset in C-AD probands was significantly earlier than in the NH-AD group and in both groups this factor was negatively associated with familial aggregation. When, for this reason, the proband samples were matched one-to-one by age at onset, dropping those probands with no match, the two curves were close to identical and the RR for the C-AD group of relatives was 1.0 The results suggest that estimates of familial risk of AD based on C-AD samples are not applicable and overestimate the extent of increased risk for relatives of more prevalent, later onset AD probands. However, the overestimate can be explained by the typically earlier age at onset in C-AD samples as opposed to a sampling bias related to the proband's family history status per se. The relationship between onset age and familial aggregation suggests that no single estimate of the age-dependent risk (survival curve) is uniformly appropriate for relatives of AD probands.     

Levetiracetam as add-on therapy in generalised epilepsies.

Levetiracetam is highly effective as add-on treatment in refractory partial-onset seizures but there are only limited data supporting its benefit in generalised epilepsies. We have reviewed the clinical records of 25 consecutive adult patients with generalised epilepsies (84% females; mean age 34 (range 16-75) years) prescribed levetiracetam for at least six months. The epilepsy was considered idiopathic in 22 patients (88%)--including 13 with juvenile myoclonic epilepsy--and symptomatic in three. Most patients (68%) reported some improvement in seizure frequency on levetiracetam including 16% who became seizure free. Levetiracetam was generally well tolerated although 11/25 (44%) of patients reported some tiredness, weight change or rash. Levetiracetam was stopped in five patients, four because of side effects and one though lack of efficacy. In four cases, pre-existing antiepileptic medication was withdrawn, leaving levetiracetam as monotherapy. We conclude that levetiracetam is a useful add-on treatment for patients with refractory generalised epilepsies.     

The Mortality Associated with Epilepsy, with Particular Reference to Sudden Unexpected Death: A Review

Summary: Recent studies indicate that the overall mortality rate for persons with epilepsy is elevated two- or threefold compared with the general population. The standardized mortality ratio (SMR) is greatest in the first few years after diagnosis and in symptomatic epilepsies. Idiopathic epilepsies also have a small increase in SMR. The sudden unexpected death rate in those with epilepsy (SUDEP) depends on the population examined. In the general population of persons with epilepsy, the risk is between 1:500 and 1:1,000 person-years. For those with severe epilepsy or other neurologic impairments, the risk appears to be 1:200 person-years. The risk in children remains uncertain. Estimates of mortality should be borne in mind when patients are counseled about the risks and benefits of various treatment strategies.     

精神分裂症和情感障碍混合家系的遗传调查

目的 探讨精神分裂症和情感障碍混合家系的遗传效应。方法 采用严格的纳入标准,应用家族史法对55例混合家系的各级亲属2134人进行详细的调查记录。分三组进行分析。结果 (1)精神分裂症为先证者组,各级亲属精神分裂症的患病率为1.1％,与1993年全国七地区调查精神分裂症的群体患病率0.655％比较,P>0.05,统计学上无显著差异,一级亲属患病率为4.79％,各群体比较,P<0.05。各级亲属情感障碍的患病率为3.78％,与1992年全国七地区调查情感障碍的群体患病0.083％比较,P<0.05,统计学上有显著差异,一级亲属患病率为17.96％。(2)情感障碍为先证者组,各级亲属情感障碍患者率为1.234％,与群体比较,P<0.05,一级亲属患病为4.76％。各级亲属精神分裂症的患病率为3.67％,与群体比较,P<0.05,一级亲属患病率为12.24％。(3)混合组,各级亲属精神分裂症的患病率为2.27％,与群体比较,P<0.05,一级亲属患病率为9.44％。结论 混合家系中,血缘关系越近,亲属中精神分裂症和情感障碍的患病率越高;精神分裂症和情感障碍在遗传传递上可能具有交叉性。     

Familial Occurrence of Epilepsy in Children with Newly Diagnosed Multiple Seizures: Dutch Study of Epilepsy in Childhood

Summary: Purpose: To study the familial occurrence of epilepsy in children with newly diagnosed multiple unprovoked seizures. Methods: Between August 1988 and September 1992, 462 children with two or more unprovoked seizures were included in the prospective Dutch Study of Epilepsy in Childhood. Seizures and epilepsy syndromes of probands were classified according to the International Classifications. Probands with at least 1 first-degree relative with epilepsy were selected. Seizures and syndromes of their relatives were classified using medical files and telephone interviews. Results: In 42% of the probands, the epilepsy was classified as localization-related, in 57% as generalized, and in 1% as undetermined whether focal or generalized. The 47 (10.2%) children with at least 1 first-degree relative with epilepsy less frequently had localization-related epilepsy (23%) and more often had generalized epilepsy (77%) as compared with the total group of probands. Fifty-eight first-degree and 21 other relatives had epilepsy. Thirty-three of the 40 (83%) first-degree relatives with idiopathic or cryptogenic epilepsy had the same seizure type as the proband, but detailed information about their seizures was sometimes difficult to obtain. Of the 12 first-degree relatives with epilepsy syndromes classifiable according to the International League Against Epilepsy (ILAE) 7 (58%) had the same syndrome as the proband. Conclusions: In 10% of children with newly diagnosed epilepsy, the condition is familial. Relatively more often, these children have generalized epilepsy syndromes as compared with children with a negative family history. Most of the relatives with idiopathic or cryptogenic epilepsy had the same sei- zure type as the proband. These findings confirm the role of genetic factors in the pathogenesis of epilepsy.     

The impact of gender and age at onset on the familial aggregation of schizophrenia

Summary Some recent family studies have shown that the familial risk for schizophrenia is higher in female than in male schizophrenics. It is debated whether the risks for the other disorders, such as schizotypal personality disorder or affective disorders in families of schizophrenics are similarly influenced by the proband's gender. Also, the reason for the effect of proband's gender on the recurrence risk for schizophrenia has not been clarified. This family study (159 probands, 589 first degree relatives) confirms that schizophrenia, but also schizophrenia spectrum disorders were more frequent in families of female compared with male schizophrenics. Neither age at onset in probands nor the interaction between gender and age at onset in probands had a relevant impact on the risk figures in relatives. Affective disorders occurred in families independently of the probands' gender. Aetiological heterogeneity or ascertainment bias may account for the modifying effect of proband's gender in schizophrenia.