Abstracts

Rationale: Neonatal epilepsies are divided into two forms, benign (familial) seizures and epileptic encephalopathies (EE). Ohtahara syndrome is a representative form of neonatal-onset EEs showing frequent tonic seizures or epileptic spasms with suppression-burst pattern on EEG and severe psychomotor developmental delay. Mutations of two genes, ARX and STXBP1, are known to be responsible for Ohtahara syndrome, while the etiology of more than half cases remains unknown. We recently performed whole-exome sequencing in 12 patients with Ohtahara syndrome and found 3 missense mutations in KCNQ2 [Saitsu et al. Ann Neurol 2012 online]. KCNQ2 was first identified as the causative gene for benign familial neonatal convulsions and then a few case reports confirmed that KCNQ2 mutations are associated with EE. A recent study by Weckhuysen et al [Ann Neurol 2012; 71(1):15-25] revealed KCNQ2 mutations in 8 patients with neonatal-onset EEs. Some patients demonstrated tonic seizures and suppression-burst suggesting Ohtahara syndrome. To unveil the clinical features of EEs caused by KCNQ2 mutations, we carried out mutation screening of KCNQ2 in patients with Ohtahara syndrome and other early-onset EEs. Methods: We performed whole-exome sequencing or high-resolution melting (HRM) analysis for KCNQ2 mutation screening in patients with Ohtahara syndrome and other early-onset EEs. Patients with brain malformations or metabolic disorders were excluded. Patients' blood samples were mainly recruited from Japanese patients and their parents following informed consent. Clinical information including EEG findings and brain MRI were also collected. The study was approved by IRB for Ethical Issues at Yokohama City University School of Medicine and Yamagata University Faculty of Medicine. Results: Whole-exome sequencing revealed additional 3 heterozygous non-synonymous KCNQ2 mutations in 3 patients and HRM analysis disclosed 5 heterozygous mutations in 6 patients. All mutations were missense and de novo. Detailed clinical information was obtained from 9 patients with KCNQ2 mutation including 3 patients described elsewhere in brief [Saitsu et al. Ann Neurol 2012 online] was analyzed. Six patients had Ohtahara syndrome characterized by tonic seizures and suppression-burst pattern on EEG. Three patients showed unclassified EE with tonic seizures in 3 and multifocal spikes in 2. All patients showed initial seizures at neonatal period, particularly within a week in 8 patients. Only 3 patients showed hypsarrhythmia on EEG and 3 patients were seizure-free treated with CBZ or PHT or TPM in each. All patients showed profound to moderate mental retardation and 5 patients were bed-ridden. Conclusions: Mutations of KCNQ2 are recurrently found in patients with Ohtahara syndrome. Patients with KCNQ2 mutation show distinct features with very early neonatal-onset, tonic seizures, suppression-burst pattern, relatively infrequent evolution to West syndrome, and good response to sodium channel blockers.