Rolandic epilepsy (RE) is the most common human epilepsy, affecting children between 3 and 12 years of age, boys more often than girls (3:2). Focal sharp waves in the centrotemporal area define the electroencephalographic (EEG) trait for the syndrome; are a feature of several related childhood epilepsies; and are freqently observed in common developmental disorders (e.g. speech dyspraxia, attention deficit hyperactivity disorder (ADHD) and developmental coordination disorder (DCD)). Here we report the first genome-wide linkage scan in RE for the EEG trait, centrotemporal sharp waves (CTS), with genomewide linkage of CTS to 11p13 (HLOD 4.30). Pure likelihood statistical analysis refined our linkage peak by fine-mapping CTS to variants in Elongator Protein Complex 4 (hELP4) in two independent datasets; the strongest evidence was with rs986527 in intron 9 of hELP4, providing a Likelihood Ratio of 629:1 (p=0.0002) in favor of an association. Resequencing of hELP4 coding, flanking and promoter regions revealed no significant exonic polymorphisms. This is the first report of a gene implicated in a common focal epilepsy and the first human disease association of hELP4. hELP4 is a component of the Elongator complex, involved in transcription and tRNA modification. Elongator depletion results in the brain-specific downregulation of genes implicated in cell motility and migration. We hypothesize that a non-coding mutation in hELP4 impairs brain-specific Elongator mediated interaction of genes implicated in brain development, resulting in susceptibility to seizures and neurodevelopmental disorders.

OXC adjunctive therapy administered in a dose range of 6 to 51 mg/kg/day (median 31.4 mg/kg/day) is safe, effective, and well tolerated in children with partial seizures.

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AIM Epilepsy is associated with difficulties in cognition and behavior in children. These problems have been attributed to genetics, ongoing seizures, psychosocial issues, underlying abnormality of the brain, and ⁄ or antiepileptic drugs. In a previous study, we found baseline cognitive differences between children with partial versus generalized and convulsive versus non-convulsive seizures. Measures in that study focused primarily on IQ scores. In the present study, we assessed baseline function with respect to new learning, attention, and memory, thus providing a more comprehensive profile than our previous study. METHODWe examined 57 children (42 females, 15 males), aged 6 to 17 years (mean 10y 1mo, SD 2y 9mo), with new-onset, idiopathic epilepsy, using tests of cognitive function reflective of new learning, memory, and attention. Seizures were classified as generalized convulsive (n=5), generalized non-convulsive (n=18), or focal (n=34). Focal seizures were divided into unilateral versus bilateral independent foci, and presence versus absence of secondary generalization.RESULTS Attention was a particular area of weakness across all groups. The Vocabulary score of an intelligence screen was higher for the focal seizure groups (p=0.012), primarily because of a difference between the unilateral focal and the primary generalized groups (p<0.047). Children with generalized, non-convulsive seizures performed significantly worse than the focal group on a measure of short-term auditory memory (p=0.019). All groups performed poorly on a test of visualmotor speed.INTERPRETATION These findings suggest intrinsic abnormalities in children with new-onset, idiopathic epilepsy at baseline.Epilepsy has been associated with difficulties in cognitive and behavioral performance in children. These problems have been attributed to an interplay of genetics, ongoing seizures, subclinical epileptiform discharges, postictal states, psychosocial issues, underlying abnormality of the brain, and the use of antiepileptic drugs. 1-9Studies attempting to identify the cause of impairment of learning and behavioral function in children with epilepsy are limited by methodological shortcomings, including variability of seizure type and etiology, absence of baseline data, polypharmacy, and attributing disturbances to antiepileptic drugs by default.10,11 Overall, there have been few prospective studies that have investigated baseline performance in children to characterize better the problems intrinsic to the epileptic condition.A study by Seidenberg et al. 12 pointed to impaired academic performance in children with epilepsy, with correlations to the number of lifetime seizure episodes, earlier onset of seizures, and multiple types of seizure. Increased rates of psychiatric problems, such as psychosis and depression, and diminished quality of life have been observed in children with epilepsy compared with typically developing children.13,14 Inattention, poor concentration, hyperactivity, and anxiety are also seen with increased frequency.15 ...