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Objective: Family members carrying the same SCN1A variant often exhibit differences in the clinical severity of epilepsy. This variable expressivity suggests that other factors aside from the primary sodium channel variant influence the clinical manifestation. However, identifying such factors has proven challenging in humans., Methods: We perform whole exome sequencing (WES) in a large family in which an SCN1A variant (p.K1372E) is segregating that is associated with a broad spectrum of phenotypes ranging from lack of epilepsy, to febrile seizures and absence seizures, to Dravet syndrome. We assessed the hypothesis that the severity of the SCN1A-related phenotype was affected by alternate alleles at a modifier locus (or loci)., Results: One of our top candidates identified by WES was a second variant in the SCN1A gene (p.L375S) that was shared exclusively by unaffected carriers of the K1372E allele. To test the hypothesized that L375S variant nullifies the loss-of-function effect of K1372E, we transiently expressed Nav1.1 carrying the two variants in HEK293T cells and compared their biophysical properties with the wild-type (WT) variant, and then co-expressed WT with K1372E or L375S with K1372E in equal quantity and tested the functional consequence. The data demonstrated that co-expression of the L375S and K1372E alleles reversed the loss-of-function property brought by the K1372E variant, whereas WT-K1372E co-expression remained partial loss-of-function., Significance: These results support the hypothesis that L375S counteracts the loss-of-function effect of K1372E such that individuals carrying both alleles in trans do not present epilepsy-related symptoms. We demonstrate that monogenic epilepsies with wide expressivity can be modified by additional variants in the disease gene, providing a novel framework for the gene-phenotype relationship in genetic epilepsies., (© 2022 International League Against Epilepsy.)

Objective: We evaluated seizure outcome in a large cohort of familial neonatal seizures (FNS), and examined phenotypic overlap with different molecular lesions., Methods: Detailed clinical data were collected from 36 families comprising two or more individuals with neonatal seizures. The seizure course and occurrence of seizures later in life were analyzed. Families were screened for KCNQ2, KCNQ3, SCN2A, and PRRT2 mutations, and linkage studies were performed in mutation-negative families to exclude known loci., Results: Thirty-three families fulfilled clinical criteria for benign familial neonatal epilepsy (BFNE); 27 of these families had KCNQ2 mutations, one had a KCNQ3 mutation, and two had SCN2A mutations. Seizures persisting after age 6 months were reported in 31% of individuals with KCNQ2 mutations; later seizures were associated with frequent neonatal seizures. Linkage mapping in two mutation-negative BFNE families excluded linkage to KCNQ2, KCNQ3, and SCN2A, but linkage to KCNQ2 could not be excluded in the third mutation-negative BFNE family. The three remaining families did not fulfill criteria of BFNE due to developmental delay or intellectual disability; a molecular lesion was identified in two; the other family remains unsolved., Significance: Most families in our cohort of familial neonatal seizures fulfill criteria for BFNE; the molecular cause was identified in 91%. Most had KCNQ2 mutations, but two families had SCN2A mutations, which are normally associated with a mixed picture of neonatal and infantile onset seizures. Seizures later in life are more common in BFNE than previously reported and are associated with a greater number of seizures in the neonatal period. Linkage studies in two families excluded known loci, suggesting a further gene is involved in BFNE., (Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.)

Objective: De novo SCN8A mutations have been reported in patients with epileptic encephalopathy. Herein we report seven patients with de novo heterozygous SCN8A mutations, which were found in our comprehensive genetic analysis (target capture or whole-exome sequencing) for early onset epileptic encephalopathies (EOEEs)., Methods: A total of 163 patients with EOEEs without mutations in known genes, including 6 with malignant migrating partial seizures in infancy (MMPSI), and 60 with unclassified EOEEs, were analyzed by target capture (28 samples) or whole-exome sequencing (135 samples)., Results: We identified de novo SCN8A mutations in 7 patients: 6 of 60 unclassified EOEEs (10.0%), and one of 6 MMPSI cases (16.7%). The mutations were scattered through the entire gene: four mutations were located in linker regions, two in the fourth transmembrane segments, and one in the C-terminal domain. The type of the initial seizures was variable including generalized tonic-clonic, atypical absence, partial, apneic attack, febrile convulsion, and loss of tone and consciousness. Onset of seizures was during the neonatal period in two patients, and between 3 and 7 months of age in five patients. Brain magnetic resonance imaging (MRI) showed cerebellar and cerebral atrophy in one and six patients, respectively. All patients with SCN8A missense mutations showed initially uncontrollable seizures by any drugs, but eventually one was seizure-free and three were controlled at the last examination. All patients showed developmental delay or regression in infancy, resulting in severe intellectual disability., Significance: Our data reveal that SCN8A mutations can cause variable phenotypes, most of which can be diagnosed as unclassified EOEEs, and rarely as MMPSI. Together with previous reports, our study further indicates that genetic testing of SCN8A should be considered in children with unclassified severe epilepsy., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Purpose: Ictal video-electroencephalography (EEG) is commonly used to establish ictal onset-zone location. Recently software development has enabled systematic studies of ictal magnetoencephalography (MEG). In this article, we evaluate the ability of ictal MEG signals to localize the seizure-onset zone., Methods: Twenty-six patients underwent ictal MEG and epilepsy surgery. Prediction of seizure-onset zone by ictal and interictal MEG was retrospectively compared with ictal-onset area found by intracranial EEG in 12 patients. The specificity and sensitivity of the prediction were calculated at hemisphere-lobe (HL) and at hemisphere-lobe-surface (HLS) levels., Key Findings: The sensitivity of ictal MEG source localization was 0.958 on HL and 0.706 on HLS levels, and its specificity was 0.900 on HL and 0.731 on HLS levels. The interictal MEG dipole cluster, defined as >10 dipoles on one lobar surface, had sensitivity of 0.400 and specificity of 0.769. Ictal MEG was equally sensitive and specific on dorsolateral and nondorsolateral neocortical surfaces up to a depth of 4 cm from the scalp., Significance: Sources of ictal-onset MEG signals and interictal dipole clusters are essentially equally specific in estimation of the ictal-onset zone on lobar surface resolution, but ictal MEG is more sensitive. On the lobe resolution, ictal MEG estimates ictal-onset zone with high sensitivity and specificity., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Purpose: Benign childhood epilepsy with centrotemporal spikes (BCECTS) is the most common epileptic syndrome in childhood. The outcome is usually excellent, but there are some atypical forms of BCECTS with less favorable outcomes. The aim of this study was to delineate the frequency of these atypical features among patients with BCECTS., Methods: We conducted a retrospective chart study by retrieving the medical records of all consecutive patients with BCECTS who were evaluated in four pediatric neurology outpatient clinics in Israel between the years 1991 and 2008., Key Findings: A total of 196 patients with BCECTS were identified (78 female and 118 male; mean age at time of diagnosis 7.64 years, range 1.5-14). The mean duration of follow-up was 4.43 years (range 2-11). Nine patients (4.6%) developed electrical status epilepticus in slow waves sleep (ESES) during follow-up, four (2%) had Landau-Kleffner syndrome, three (1.5%) had BCECTS with frequent refractory seizures, two (1%) had BCECTS with falls at presentation, one (0.5%) had a "classic" atypical variant, and one (0.5%) had oromotor dysfunction. None had rolandic status epilepticus. Sixty-one patients (31%) had attention deficit hyperactivity disorder (ADHD), 43 (21.9%) had specific cognitive deficits, and 23 (11.7%) had behavioral abnormalities, including aggressiveness, anxiety disorders, depression, and pervasive developmental disorder (PDD)., Significance: The prevalence of most atypical forms of BCECTS other than ESES is low. There is, however, a high prevalence of ADHD and specific cognitive deficits among patients with BCECTS., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Purposes: To describe the clinical spectrum and to evaluate the efficacy of different therapeutic agents in children with electrical status epilepticus in sleep (ESES)., Methods: Clinical data of all patients with ESES (not including patients with Landau-Kleffner syndrome) in four pediatric neurology outpatient clinics were analyzed. Thirty patients with ESES had been treated between 1994 and 2007., Results: Eleven (37%) children had benign partial epilepsies of childhood, five (17%) had cerebral palsy, five (17%) had hydrocephalus, one (3%) had schizencephaly, one (3%) had prenatal parenchymal bleeding, and the etiology was unclear in seven (23%). The duration of ESES ranged between 2 and 60 months. The antiepileptic drugs that were found to be efficacious were: levetiracetam (41%), clobazam (31%), and sulthiame (17%). Valproic acid, lamotrigine, topiramate, and ethosuximide showed no efficacy. Steroids were efficacious in 65%; immunoglobulins were efficacious in 33%. High-dose diazepam was efficacious in 37%, but all the children had temporary response. Seventeen patients (57%) had cognitive deterioration, whereas the rest presented with regression in attention, speech, communication, and behavior. Fourteen children had permanent cognitive deficit. There was a significant correlation (p = 0.029) between the duration of ESES and residual intellectual deficit at follow-up., Conclusions: ESES reflects an evolution of benign partial epilepsy of childhood in more than one-third of the patients, whereas there is an underlying structural brain anomaly in another one-third. The most efficacious antiepileptic drugs (AEDs) are levetiracetam and clobazam. The duration of ESES correlated significantly with residual intellectual deficit at follow-up.

Purpose: To investigate the effect of epilepsy and/or valproate (VPA) monotherapy on physical growth, weight gain, pubertal development, and hormonal status in adolescent girls with epilepsy., Methods: The study group included 88 consecutive female patients with epilepsy aged 6-20 years (28 premenarche, 60 postmenarche) attending an endocrinology institute of a major tertiary center. Forty-five patients were under treatment with VPA, and 43 were before treatment initiation. The groups were compared for the relevant biochemical, anthropometric, ultrasonographic, and endocrine parameters., Results: No statistically significant differences were found in any of the parameters studied between the groups, as a whole or by menarche status. The treated postmenarcheal subgroup had a higher mean testosterone level than the untreated postmenarcheal controls (1.83 +/- 0.65 vs. 0.88 +/- 0.24, p=0.006). Body mass index--standard deviation score (BMI-SDS) was 0.75 in the treated group and 0.63 in the untreated group; rates of obesity were 16.3% and 15.5%, respectively. No between-group differences were found in menses irregularities, hirsutism, or acne. No correlation was found between duration or dosage of treatment and BMI-SDS, height-SDS, or androgen level. The treated group had higher levels of thyroid-stimulating hormone and lower levels of free thyroxine than did the untreated group, although still within normal range., Conclusions: Long-term treatment with VPA in girls with epilepsy is associated with increased testosterone levels after menarche, without clinical hyperandrogenism, polycystic ovary syndrome, or an increase in BMI-SDS. VPA is a good treatment option in this age group but should be accompanied by careful endocrine observation.