RESUMO
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.
Assuntos
Cromossomos Humanos Par 10 , Epilepsias Parciais/genética , Adolescente , Adulto , Mapeamento Cromossômico , Feminino , Ligação Genética , Marcadores Genéticos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
BACKGROUND: In epilepsy as in other disorders, family history information is often obtained by asking patients about the medical histories of their relatives rather than interviewing or examining the relatives directly. The accuracy of this type of information for epilepsy and other seizure disorders is unclear. METHODS: This study used data from the Genetic Epidemiology of Seizure Disorders in Rochester study, a population-based investigation including all Rochester, MN, residents born ≥1920 with incidence of unprovoked seizures from 1935 to 1994 (case probands) and control probands matched by age, gender, and prior Rochester residency period. Seizure disorders in the first-degree relatives of case and control probands were ascertained by reviewing the relatives' medical records. Case and control probands were interviewed about seizures in their first-degree relatives using a validated 9-question screening interview. Interviewers were blinded to case-control status. RESULTS: Sensitivity of the family history (i.e., proportion of relatives with medical record-documented seizures who screened positive in the proband interview) was 62% (32/52) for epilepsy, 50% (7/14) for isolated unprovoked seizures, and 56% (9/16) for febrile seizures. Sensitivity did not differ by case/control status of the proband. Sensitivity was much higher for probands reporting on their offspring or siblings than their parents. Among relatives with epilepsy, 90% of offspring and 80% of siblings but only 32% of parents screened positive. CONCLUSIONS: Family histories of epilepsy are reasonably accurate for siblings and offspring, but are underreported in parents. Family histories of other seizure disorders are underreported.
Assuntos
Epilepsia/psicologia , Anamnese , Inquéritos e Questionários , Estudos de Casos e Controles , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with extremely variable expressivity. Mutations in 5 genes that raise susceptibility to GEFS+ have been discovered, but they account for only a small proportion of families. METHODS: We identified a 4-generation family containing 15 affected individuals with a range of phenotypes in the GEFS+ spectrum, including febrile seizures, febrile seizures plus, epilepsy, and severe epilepsy with developmental delay. We performed a genome-wide linkage analysis using microsatellite markers and then saturated the potential linkage region identified by this screen with more markers. We evaluated the evidence for linkage using both model-based and model-free (posterior probability of linkage [PPL]) analyses. We sequenced 16 candidate genes and screened for copy number abnormalities in the minimal genetic region. RESULTS: All 15 affected subjects and 1 obligate carrier shared a haplotype of markers at chromosome 6q16.3-22.31, an 18.1-megabase region flanked by markers D6S962 and D6S287. The maximum multipoint lod score in this region was 4.68. PPL analysis indicated an 89% probability of linkage. Sequencing of 16 candidate genes did not reveal a causative mutation. No deletions or duplications were identified. CONCLUSIONS: We report a novel susceptibility locus for genetic epilepsy with febrile seizures plus at 6q16.3-22.31, in which there are no known genes associated with ion channels or neurotransmitter receptors. The identification of the responsible gene in this region is likely to lead to the discovery of novel mechanisms of febrile seizures and epilepsy.
Assuntos
Cromossomos Humanos Par 6/genética , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Convulsões Febris/genética , Adolescente , Adulto , Criança , Pré-Escolar , Família , Feminino , Dosagem de Genes , Ligação Genética , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Linhagem , Síndrome , Adulto JovemRESUMO
OBJECTIVE: To evaluate the influence of ethnicity on the use of peritoneal dialysis (PD) as initial treatment for end-stage renal disease (ESRD) after controlling for other patient characteristics. DESIGN: Inception cohort analysis of incident ESRD patients. PATIENTS: All African-American and white patients (N = 10,726) who began treatment for ESRD at dialysis centers in North Carolina, South Carolina, and Georgia and reported to ESRD Network 6 between January 1, 1989, and December 31, 1991. MAIN OUTCOME MEASURE: Odds ratios (ORs) of the association between ethnicity and PD as initial treatment modality. RESULTS: African-American patients were 56% less likely than whites to use PD (OR, 0.44; 95% confidence interval [CI], 0.40 to 0.49). This difference persisted (OR, 0.45; 95% CI, 0.38 to 0.52) after multivariable adjustment for age, education, social support, home ownership, functional status, albumin level, hypertension, history of myocardial infarction, peripheral neuropathy, and comorbid diabetes. CONCLUSIONS: Ethnic differences in initial PD use cannot be explained by many demographic, socioeconomic, and comorbid factors associated with the use of PD as initial treatment for ESRD.
Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Falência Renal Crônica/etnologia , Diálise Peritoneal/estatística & dados numéricos , População Branca/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Comorbidade , Feminino , Georgia/epidemiologia , Humanos , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , North Carolina/epidemiologia , Razão de Chances , Fatores Socioeconômicos , South Carolina/epidemiologiaRESUMO
We used POINTER to perform segregation analysis of cryptogenic epilepsy in 1,557 three-generation families (probands and their parents, siblings, and offspring) ascertained from voluntary organizations. Analysis of the full data set indicated that the data were most consistent with an autosomal dominant (AD) model with 61% penetrance of the susceptibility gene. However, subsequent analyses revealed that the patterns of familial aggregation differed markedly between siblings and offspring of the probands. Risks in siblings were consistent with an autosomal recessive (AR) model and inconsistent with an AD model, whereas risks in offspring were inconsistent with an AR model and more consistent with an AD model. As a further test of the validity of the AD model, we used sequential ascertainment to extend the family history information in the subset of families judged likely to carry the putative susceptibility gene because they contained at least three affected individuals. Prevalence of idiopathic/cryptogenic epilepsy was only 3.7% in newly identified relatives expected to have a 50% probability of carrying the susceptibility gene under an AD model. Approximately 30% (i.e., 50% x 61%) were expected to be affected under the AD model resulting from the segregation analysis. These results suggest that the familial distribution of cryptogenic epilepsy is inconsistent with any conventional genetic model. The differences between siblings and offspring in the patterns of familial risk are intriguing and should be investigated further.
Assuntos
Epilepsia/genética , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Lactente , Pessoa de Meia-Idade , Modelos Genéticos , Modelos Estatísticos , Fenótipo , Fatores de RiscoRESUMO
OBJECTIVE: S: Mutations in LGI1 cause autosomal dominant partial epilepsy with auditory features (ADPEAF), a form of familial temporal lobe epilepsy with auditory ictal manifestations. The authors aimed to determine what proportion of ADPEAF families carries a mutation, to estimate the penetrance of identified mutations, and to identify clinical features that distinguish families with and without mutations. METHODS: The authors sequenced LGI1 in 10 newly described ADPEAF families and analyzed clinical features in these families and others with mutations reported previously. RESULTS: Three of the families had missense mutations in LGI1 (C42R, I298T, and A110D). Penetrance was 54% in eight families with LGI1 mutations the authors have identified so far (five reported previously and three reported here). Excluding the original linkage family, the authors have found mutations in 50% (7/14) of tested families. Families with and without mutations had similar clinical features, but those with mutations contained significantly more subjects with auditory symptoms and significantly fewer with autonomic symptoms. In families with mutations, the most common auditory symptom type was simple, unformed sounds (e.g., buzzing and ringing). In two of the newly identified families with mutations, some subjects with mutations had idiopathic generalized epilepsies. CONCLUSIONS: LGI1 mutations are a common cause of autosomal dominant partial epilepsy with auditory features. Current data do not reveal a clinical feature that clearly predicts which families with autosomal dominant partial epilepsy with auditory features have a mutation. Some families with LGI1 mutations contain individuals with idiopathic generalized epilepsies. This could result from either an effect of LGI1 on risk for generalized epilepsy or an effect of co-occurring idiopathic generalized epilepsy-specific genes in these families.