Nine patients with KCNQ2-related neonatal seizures and functional studies of two missense variants.

Mutations in KCNQ2 encoding for voltage-gated K channel subunits underlying the neuronal M-current have been associated with infantile-onset epileptic disorders. The clinical spectrum ranges from self-limited neonatal seizures to epileptic encephalopathy and delayed development. Mutations in KCNQ2 could be either gain- or loss-of-function which require different therapeutic approaches. To better understand genotype-phenotype correlation, more reports of patients and their mutations with elucidated molecular mechanism are needed. We studied 104 patients with infantile-onset pharmacoresistant epilepsy who underwent exome or genome sequencing. Nine patients with neonatal-onset seizures from unrelated families were found to harbor pathogenic or likely pathogenic variants in the KCNQ2 gene. The p.(N258K) was recently reported, and p. (G279D) has never been previously reported. Functional effect of p.(N258K) and p.(G279D) has never been previously studied. The cellular localization study demonstrated that the surface membrane expression of Kv7.2 carrying either variant was decreased. Whole-cell patch-clamp analyses revealed that both variants significantly impaired Kv7.2 M-current amplitude and density, conductance depolarizing shift in voltage dependence of activation, membrane resistance, and membrane time constant (Tau), indicating a loss-of-function in both the homotetrameric and heterotetrameric with Kv7.3 channels. In addition, both variants exerted dominant-negative effects in heterotetrameric with Kv7.3 channels. This study expands the mutational spectrum of KCNQ2- related epilepsy and their functional consequences provide insights into their pathomechanism.

Proteomic analysis reveals plasma haptoglobin, interferon-γ, and interleukin-1ß as potential biomarkers of pediatric refractory epilepsy.

BACKGROUND: Children with refractory epilepsy (RE) are associated with increased mortality rate, nonfatal injuries, disability, and diminished quality of life. Biomarkers for the early prediction of RE is still an unmet need. METHODS: Eighteen children with RE and six age-matched unrelated controls were included in this study. Plasma samples were prefractionated by the optimized thermal treatment before proteomic analysis using 2DE-LC-MS/MS. Bioinformatic analysis was carried out using STRING protein network. Immunoassay of unprocessed plasma was applied to confirm changes of proteins of interest. P-value < 0.05 was considered statistically significant. RESULTS: Proteomic analysis (n = 6 each group) revealed nine differentially expressed proteins, i.e., haptoglobin, S100A9, serpin B1, apolipoprotein A-I, apolipoprotein A-IV, apolipoprotein C-II, alpha-1-acid glycoprotein 1 and 2, and transthyretin. Western immunoblotting confirmed haptoglobin upregulation in the RE group. STRING protein network predicted the inflammatory cytokines, i.e., interferon gamma (IFN-γ), interleukin-1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α), play roles in pathophysiology in RE patients. Cytokine immunoassay (n = 24, 18 RE vs. 6 controls) exhibited plasma IFN-γ was upregulated in RE patients as compared to the healthy individuals (median [IQR]; 2.9 [2.9, 4.9] vs. 1.32 [0.8, 1.5] pg/mL, p = 0.0013), and plasma IL-1ß was significantly downregulated in patients (1.0 [0.2, 1.9] vs. 4.5 [1.9, 11.0] pg/mL, p = 0.01). TNF-α had no difference between groups. The results suggest that haptoglobin may be associated with oxidative brain damage, while IFN-γ and IL-1ß may be involved with neuroinflammation. CONCLUSIONS: Alterations in plasma haptoglobin, IFN-γ, and IL-1ß were associated with RE patients. Future studies using a combination of these candidate biomarkers may help predict the intractability of epilepsy in pediatric populations.

Epilepsy video animation: Impact on knowledge and drug adherence in pediatric epilepsy patients and caregivers.

OBJECTIVES: Insufficient of knowledge of epilepsy causes poor drug adherence and seizure control. Leading us to create video animation to educate epilepsy patients and caregivers and evaluate the benefit of this video. PATIENTS AND METHODS: The 8.52-min video animation was created to provide fundamental information regarding diagnosis, treatment and drug usage for pediatric epilepsy patients. The impact of this video animation was evaluated in a randomized controlled trial (RCT) study during June- September 2016. One month to 15 year-old epilepsy patients and caregivers were recruited and randomized into 2 groups; group A: receiving advice from the clinician and watching the video animation, group B: only receiving advice from the clinician. A ten-item questionnaires and drug adherence (Morisky Medication Adherence Scales (MMAS-8)) were used to evaluate before/after watching video/receiving advice and at 3 month-follow up. RESULTS: Two hundreds and fourteen epilepsy patients (126 in group A and 88 in group B) were recruited in the study. Before watching video/receiving advice, the mean scores of questionnaires in group A was lower compare with the group B (group A (6.74) and group B (7.38)) but after the video intervention the score of group A significantly rose to 7.42 (immediate after watching video) and to 7.47 scores at 3 month-follow up, while in group B, no significant differences were observed. The comparison of the MMAS-8 in group A showed a significant improvement of drug adherence than the cases in group B. CONCLUSION: Video animation as a new method of education for epilepsy patients and caregivers, can improve both their knowledge and the drug adherence.