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Autosomal dominant mutations in the sodium-gated potassium channel subunit gene KCNT1 have been associated with two distinct seizure syndromes, nocturnal frontal lobe epilepsy (NFLE) and malignant migrating focal seizures of infancy (MMFSI). To further explore the phenotypic spectrum associated with KCNT1, we examined individuals affected with focal epilepsy or an epileptic encephalopathy for mutations in the gene. We identified KCNT1 mutations in 12 previously unreported patients with focal epilepsy, multifocal epilepsy, cardiac arrhythmia, and in a family with sudden unexpected death in epilepsy (SUDEP), in addition to patients with NFLE and MMFSI. In contrast to the 100% penetrance so far reported for KCNT1 mutations, we observed incomplete penetrance. It is notable that we report that the one KCNT1 mutation, p.Arg398Gln, can lead to either of the two distinct phenotypes, ADNFLE or MMFSI, even within the same family. This indicates that genotype-phenotype relationships for KCNT1 mutations are not straightforward. We demonstrate that KCNT1 mutations are highly pleiotropic and are associated with phenotypes other than ADNFLE and MMFSI. KCNT1 mutations are now associated with Ohtahara syndrome, MMFSI, and nocturnal focal epilepsy. They may also be associated with multifocal epilepsy and cardiac disturbances., (Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.)

Mutations of the SCN1A subunit of the sodium channel is a cause of genetic epilepsy with febrile seizures plus (GEFS(+) ) in multiplex families and accounts for 70-80% of Dravet syndrome (DS). DS cases without SCN1A mutation inherited have predicted SCN9A susceptibility variants, which may contribute to complex inheritance for these unexplained cases of DS. Compared with controls, DS cases were significantly enriched for rare SCN9A genetic variants. None of the multiplex febrile seizure or GEFS(+) families could be explained by highly penetrant SCN9A mutations., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Heterozygous mutations in PRRT2 have recently been identified as the major cause of autosomal dominant benign familial infantile epilepsy (BFIE), infantile convulsions with choreoathetosis syndrome (ICCA), and paroxysmal kinesigenic dyskinesia (PKD). Homozygous mutations in PRRT2 have also been reported in two families with intellectual disability (ID) and seizures. Heterozygous mutations in the genes KCNQ2 and SCN2A cause the two other autosomal dominant seizure disorders of infancy: benign familial neonatal epilepsy and benign familial neonatal-infantile epilepsy. Mutations in KCNQ2 and SCN2A also contribute to severe infantile epileptic encephalopathies (IEEs) in which seizures and intellectual disability co-occur. We therefore hypothesized that PRRT2 mutations may also underlie cases of IEE. We examined PRRT2 for heterozygous, compound heterozygous or homozygous mutations to determine their frequency in causing epileptic encephalopathies (EEs). Two hundred twenty patients with EEs with onset by 2 years were phenotyped. An assay for the common PRRT2 c.649-650insC mutation and high resolution-melt analysis for mutations in the remaining exons of PRRT2 were performed. Neither the common mutation nor any other pathogenic variants in PRRT2 were detected in the 220 patients. Our findings suggest that mutations in PRRT2 are not a common cause of IEEs., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Purpose: Mutations of the SCARB2 gene cause action myoclonus renal failure syndrome (AMRF), a rare condition that combines progressive myoclonus epilepsy (PME) with severe renal dysfunction. We describe the clinical and neurophysiologic features of PME associated with SCARB2 mutations without renal impairment., Methods: Clinical and neurophysiologic investigations, including wakefulness and sleep electroencephalography (EEG), polygraphic recording (with jerk-locked back-averaging and analysis of the EEG-EMG (electromyography) relationship by coherence spectra and phase calculation), multimodal evoked potentials, and electromyography were performed on five Italian patients with SCARB2 mutations., Key Findings: The main clinical features were adolescent-young adulthood onset, progressive action myoclonus, ataxia, absence of cognitive deterioration and, in most cases, epilepsy. The severity of the epilepsy could vary from uncontrolled seizures and status epilepticus in patients with adolescent onset to absent or rare seizures in patients with adult onset. Relevant neurophysiologic findings were a pronounced photosensitivity and massive action myoclonus associated with rhythmic myoclonic jerks at a frequency of 12-20 Hz, clinically resembling a postural tremor. The cortical origin of rhythmic myoclonus was demonstrated mainly by coherence and phase analysis of EEG-EMG signals indicating a significant EEG-EMG coupling and a direct corticospinal transfer., Significance: Our patients with SCARB2 mutations showed the clinical and neurophysiologic phenotype of PME, in which epilepsy could be extremely severe, extending the spectrum reported in the typical AMRF syndrome. Patients with PME of unknown origin of adolescent or young adult onset, with these neurophysiologic features, should be tested for SCARB2 mutations, even in the absence of renal impairment., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Incomplete penetrance and variable phenotypic expression are characteristic of a number of syndromes of familial epilepsy. The purpose of the present investigation is to determine if the 15q13.3 copy number deletion functions as a locus modifying the epilepsy phenotype caused by other known or presumed pathogenic mutations segregating in families with epilepsies. No 15q13.3 microdeletions were detected in 756 affected or definite obligate carrier individuals across 151 families selected on the basis of having multiple members affected with epilepsy and showing a range of seizure types. Therefore, the 15q13.3 microdeletion does not act as a genetic modifier in this cohort of families and is not responsible for any of the genetic heterogeneity hypothesized to account for failure to detect linkage in previous genome-wide scans in five of the larger families included in this study., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Objective: We aimed to determine the type, frequency, and size of microchromosomal copy number variations (CNVs) affecting the neuronal sodium channel α 1 subunit gene (SCN1A) in Dravet syndrome (DS), other epileptic encephalopathies, and generalized epilepsy with febrile seizures plus (GEFS+)., Methods: Multiplex ligation-dependent probe amplification (MLPA) was applied to detect SCN1A CNVs among 289 cases (126 DS, 97 GEFS+, and 66 with other phenotypes). CNVs extending beyond SCN1A were further characterized by comparative genome hybridization (array CGH)., Results: Novel SCN1A CNVs were found in 12.5% of DS patients where sequence-based mutations had been excluded. We identified the first partial SCN1A duplications in two siblings with typical DS and in a patient with early-onset symptomatic generalized epilepsy. In addition, a patient with DS had a partial SCN1A amplification of 5-6 copies. The remaining CNVs abnormalities were four partial and nine whole SCN1A deletions involving contiguous genes. Two CNVs (a partial SCN1A deletion and a duplication) were inherited from a parent, in whom there was mosaicism. Array CGH showed intragenic deletions of 90 kb and larger, with the largest of 9.3 Mb deleting 49 contiguous genes and extending beyond SCN1A., Discussion: Duplication and amplification involving SCN1A are now added to molecular mechanisms of DS patients. Our findings showed that 12.5% of DS patients who are mutation negative have MLPA-detected SCN1A CNVs with an overall frequency of about 2-3%. MLPA is the established second-line testing strategy to reliably detect all CNVs of SCN1A from the megabase range down to one exon. Large CNVs extending outside SCN1A and involving contiguous genes can be precisely characterized by array CGH.

Purpose: To identify genes involved in idiopathic absence epilepsies by analyzing gene expression using a monozygotic (MZ) twin design., Methods: Genome-wide gene expression in lymphoblastoid cell lines (LCLs) was determined using microarrays derived from five discordant and four concordant MZ twin pairs with idiopathic absence epilepsies and five unaffected MZ twin pairs. Gene expression was analyzed using three strategies: discordant MZ twins were compared as matched pairs, MZ twins concordant for epilepsy were compared to control MZ twins, and a singleton design of affected versus unaffected MZ twin individuals was used irrespective of twin pairing. An overlapping gene list was generated from these analyses. Dysregulation of genes recognized from the microarray experiment was validated using quantitative real time PCR (qRT-PCR) in the twin sample and in an independent sample of 18 sporadic absence cases and 24 healthy controls., Results: Sixty-five probe sets were identified from the three combined microarray analysis strategies. Sixteen genes were chosen for validation and nine of these genes confirmed by qRT-PCR in the twin sample. Differential expression for EGR1 (an immediate early gene) and RCN2 (coding for the calcium-binding protein Reticulocalbin 2) were reconfirmed by qRT-PCR in the independent sample., Discussion: Using a unique sample of discordant MZ twins, our study identified genes with altered expression, which suggests novel mechanisms in idiopathic absence epilepsy. Dysregulation of EGR1 and RCN2 is implicated in idiopathic absence epilepsy.

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 alpha1 and gamma 2 gamma-aminobutyric acid (GABA)-receptor subunits, alpha1 and beta1 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.