Abstracts

Rationale: Since the first report of STXBP1 mutations in 5 patients with Ohtahara syndrome (OS), various phenotypes, such as West syndrome (WS), Lennox-Gastaut syndrome, Dravet syndrome, unclassified early-onset epileptic encephalopathy (EOEE), and intellectual disability without epilepsy, have been identified and have been recently designated as 'STXBP1 encephalopathy'. To delineate the clinical features associated with STXBP1 mutations, we reviewed the characteristics of epilepsy and neurological findings, particularly the efficacy of medications. Methods: A total of 223 Japanese patients with EOEE including 41 OS and 115 WS cases were analyzed for the STXBP1 mutation as a third cohort using high-resolution melt analysis, targeted capture and sequencing, or whole-exome sequencing. We collected medical records from all patients with the STXBP1 mutation including follow-up records of 18 patients with STXBP1 mutation reported previously. The efficacy of medications was evaluated using patient response rate by comparing the seizure frequency or EEG data before and after the treatment. Patients who showed a seizure reduction of more than 50 % in frequency or disappearance of a characteristic pattern on EEG, such as suppression-burst or hypsarrhythmia, were defined as responders. Results: Twelve mutations were discovered newly in 14 patients. All mutations were occurred de novo. Together with 18 patients we published previously, missense mutations were found in 11 patients, nonsense mutations in 8, splicing mutations in 7, large deletions in 4, and frameshift mutations in 2. The average age of the patients was 6.7 ± 7.8 years (4 months to 44 years). The initial diagnosis was OS in 29 patients, unclassified EOEE in 2, and WS in 1. All but 1 patient showed epileptic spasms at the age of 1.7 ± 1.2 months (2 days to 5 months). 22 patients showed hypsarrhythmia on EEG during their clinical course and 20 of 29 (69%) of OS evolved to WS. 15 patients under medication experienced disappearance of seizures at least once, and 7 remained seizure free. The frequently used epilepsy medications were VPA (94%), ZNS (88%), and ACTH (81%), and the response rate of ACTH (85%), TPM (62%), and high-dose PB (57%) for seizure frequency was greater than that of other medications. The response rate for EEG improvement was also good in the ACTH (70%) and high-dose PB (67%) groups, but not in the TPM (8%) group. The response rate to LEV was 31% and 10% for seizure frequency and EEG improvement, respectively. 28 patients older than 12 months showed profound intellectual disability. Only 1 patient was ambulant, 1 could stand with support, and 2 could sit alone. Two patients showed sudden unexpected death at the age of 28 months and 9 years, respectively. Conclusions: STXBP1 mutations predominantly cause OS followed by WS. The onset of spasms was relatively later than in other patients with OS caused by KCNQ2 or SCN2A mutations. While ACTH and high-dose PB could be recommended for treatment, seizures are intractable in most patients and neurological prognosis is poor. SUDEP should be noticed.