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.
In a retrospective study of 59 children (ages 9 months to 23 years; mean age 11 years) with intractable epilepsy, seizure frequency was determined before and after 12 months of levetiracetam therapy. Charts were reviewed for seizure type (focal, generalized, or mixed), cognitive function (no special education versus special education), concomitant anticonvulsant medications (range 0-5), and the number of previous anticonvulsant drugs (range 1-12). Good to excellent seizure control (50-100% reduction) was attained in 6 (40%) patients with focal seizures, 16 (55%) patients with generalized seizures, and 8 (61%) patients with mixed seizures; these efficacy rates were not significantly different. The efficacy of levetiracetam was independent of cognitive status. Adverse effects were not associated with higher mean doses. This could be attributable to different rates of metabolism or represent idiosyncratic responses to the medication. Our finding that those children taking the combination of levetiracetam and zonisamide had a significantly worse outcome than those on levetiracetam and a different drug warrants further study, both clinically and from the standpoint of the mechanisms of action of levetiracetam and zonisamide and/or their pharmacodynamic interactions.
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