Purpose: In families with idiopathic generalized epilepsy (IGE), multiple IGE subsyndromes may occur. We performed a genetic study of IGE families to clarify the genetic relation of the IGE ...subsyndromes and to improve understanding of the mode(s) of inheritance.
Methods: Clinical and genealogic data were obtained on probands with IGE and family members with a history of seizures. Families were grouped according to the probands' IGE subsyndrome: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with tonic–clonic seizures only (IGE‐TCS). The subsyndromes in the relatives were analyzed. Mutations in genes encoding α1 and γ2 γ‐aminobutyric acid (GABA)‐receptor subunits, α1 and β1 sodium channel subunits, and the chloride channel CLC‐2 were sought.
Results: Fifty‐five families were studied. 122 (13%) of 937 first‐ and second‐degree relatives had seizures. Phenotypic concordance within families of CAE and JME probands was 28 and 27%, respectively. JAE and IGE‐TCS families had a much lower concordance (10 and 13%), and in the JAE group, 31% of relatives had CAE. JME was rare among affected relatives of CAE and JAE probands and vice versa. Mothers were more frequently affected than fathers. No GABA‐receptor or sodium or chloride channel gene mutations were identified.
Conclusions: The clinical genetic analysis of this set of families suggests that CAE and JAE share a close genetic relation, whereas JME is a more distinct entity. Febrile seizures and epilepsy with unclassified tonic–clonic seizures were frequent in affected relatives of all IGE individuals, perhaps representing a nonspecific susceptibility to seizures. A maternal effect also was seen. Our findings are consistent with an oligogenic model of inheritance.
To analyze the clinical syndromes and inheritance patterns of multiplex families with epilepsy toward the ultimate aim of uncovering the underlying molecular genetic basis.
Following the referral of ...families with 2 or more relatives with epilepsy, individuals were classified into epilepsy syndromes. Families were classified into syndromes where at least 2 family members had a specific diagnosis. Pedigrees were analyzed and molecular genetic studies were performed as appropriate.
A total of 211 families were ascertained over an 11-year period in Israel. A total of 169 were classified into broad familial epilepsy syndrome groups: 61 generalized, 22 focal, 24 febrile seizure syndromes, 33 special syndromes, and 29 mixed. A total of 42 families remained unclassified. Pathogenic variants were identified in 49/211 families (23%). The majority were found in established epilepsy genes (e.g., SCN1A, KCNQ2, CSTB), but in 11 families, this cohort contributed to the initial discovery (e.g., KCNT1, PCDH19, TBC1D24). We expand the phenotypic spectrum of established epilepsy genes by reporting a familial LAMC3 homozygous variant, where the predominant phenotype was epilepsy with myoclonic-atonic seizures, and a pathogenic SCN1A variant in a family where in 5 siblings the phenotype was broadly consistent with Dravet syndrome, a disorder that usually occurs sporadically.
A total of 80% of families were successfully classified, with pathogenic variants identified in 23%. The successful characterization of familial electroclinical and inheritance patterns has highlighted the value of studying multiplex families and their contribution towards uncovering the genetic basis of the epilepsies.
Summary
Paroxysmal exercise‐induced dyskinesia (PED) and epilepsy without intellectual disability have recently been recognized as manifestations of deficiency of the glucose transporter GLUT1, due ...to mutations in the gene SLC2A1. We describe a family with six definitely affected members in two generations. Two had PED, three had epilepsy, and one had both. A missense mutation in SLC2A1 (c.950A>C; p.N317T) was detected in five living affected members, but absent in three nonaffected first‐degree members and in one subject believed to be a phenocopy. The clinical picture of mild epilepsy with onset in adolescence or early adulthood plus PED should raise a suspicion of GLUT1 deficiency.
Purpose: This study examined the influence of two psychosocial variables mediating between disease severity and quality of life (Qol) in epilepsy; social support and mastery (measured by locus of ...control and self‐efficacy). A model placing these two variables as mediators between disease severity and QoL was tested with structural equation modeling.
Methods: Eighty‐nine patients with epilepsy (58% men, age 36 ± 12 years) were given the following instruments: Liverpool Seizure Severity Scale, Interpersonal Support Evaluation List, Epileptic Self‐Efficacy Scale, Locus of Control scale, and the World Health Organization's Quality of Life Questionnaire, the WHOQOL.
Results: Structural equation modeling showed good fit between the research model and the data (Bentler‐Bonett Normalized Index of fit, 0.96; LISREL GFI, 0.95). Ninety percent of the variance of the WHOQOL was explained by a combination of disease severity, self‐efficacy in epilepsy, social support, and locus of control. Mastery was found to mediate the correlation between disease severity and QoL, and social support was found to act as a mediator between disease severity and mastery.
Conclusions: The study findings emphasize the possibility of improving QoL among patients with epilepsy by counseling and treatment aimed at reinforcing their self‐efficacy and locus of control, as well as by improving their SoS.
Localizing the source of an epileptic seizure using noninvasive EEG suffers from inaccuracies produced by other generators not related to the epileptic source. The authors isolated the ictal ...epileptic activity, and applied a source localization algorithm to identify its estimated location. Ten ictal EEG scalp recordings from five different patients were analyzed. The patients were known to have temporal lobe epilepsy with a single epileptic focus that had a concordant MRI lesion. The patients had become seizure-free following partial temporal lobectomy. A midinterval (approximately 5 seconds) period of ictal activity was used for Principal Component Analysis starting at ictal onset. The level of epileptic activity at each electrode (i.e., the eigenvector of the component that manifest epileptic characteristic), was used as an input for low-resolution tomography analysis for EEG inverse solution (Zilberstain et al., 2004). The algorithm accurately and robustly identified the epileptic focus in these patients. Principal component analysis and source localization methods can be used in the future to monitor the progression of an epileptic seizure and its expansion to other areas.
Progressive myoclonus epilepsy (PME) has a number of causes, of which Unverricht–Lundborg disease (ULD) is the most common. ULD has previously been mapped to a locus on chromosome 21 (EPM1). ...Subsequently, mutations in the cystatin B gene have been found in most cases. In the present work we identified an inbred Arab family with a clinical pattern compatible with ULD, but mutations in the cystatin B gene were absent. We sought to characterize the clinical and molecular features of the disorder. The family was studied by multiple field trips to their town to clarify details of the complex consanguineous relationships and to personally examine the family. DNA was collected for subsequent molecular analyses from 21 individuals. A genome-wide screen was performed using 811 microsatellite markers. Homozygosity mapping was used to identify loci of interest. There were eight affected individuals. Clinical onset was at 7.3 ± 1.5 years with myoclonic or tonic–clonic seizures. All had myoclonus that progressed in severity over time and seven had tonic–clonic seizures. Ataxia, in addition to myoclonus, occurred in all. Detailed cognitive assessment was not possible, but there was no significant progressive dementia. There was intrafamily variation in severity; three required wheelchairs in adult life; the others could walk unaided. MRI, muscle and skin biopsies on one individual were unremarkable. We mapped the family to a 15-megabase region at the pericentromeric region of chromosome 12 with a maximum lod score of 6.32. Although the phenotype of individual subjects was typical of ULD, the mean age of onset (7.3 years versus 11 years for ULD) was younger. The locus on chromosome 12 does not contain genes for any other form of PME, nor does it have genes known to be related to cystatin B. This represents a new form of PME and we have designated the locus as EPM1B.
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