Abstracts

Rationale: Variants in the KCNQ2 gene encoding for Kv7.2 potassium (K+) channel subunits are responsible for a wide spectrum of epileptic diseases, ranging from self-limiting benign familial neonatal epilepsy (BFNE; OMIM: 121200) to neonatal-onset severe epileptic encephalopathy (EIEE7, OMIM: 613720). Given such phenotypic heterogeneity, comparing histories of patients carrying the same KCNQ2 variant provides the unique opportunity to assess the variant pathogenetic role, and to correlate the specific variant with the disease clinical course and severity. The aim of the present study has been to describe the case histories of four unrelated patients carrying the same de novo KCNQ2 missense variant (c.593G>A) leading to the p.R198Q substitution, and to assess some of the functional properties of channels carrying the R198 substitution. Methods: Via the Rational Intervention for KCNQ2/3 Epileptic Encephalopathy (RIKEE) database, an  international registry currently edited and maintained at Baylor College of Medicine under an IRB approved research protocol, four unrelated patients were identified with de novo heterozygous KCNQ2 c.593G>A, p.R198Q variants.  This variants was engineered in human KCNQ2 cDNA, and channels carrying mutant subunits were heterologously expressed by transient transfection in Chinese Hamster Ovary (CHO) cells, where macroscopic currents were recorded using the whole-cell patch-clamp technique. R198Q mutant subunits were also expressed in primary cultures of rat hippocampal neurons to investigate their subcellular distribution by confocal immunocytochemistry. Results: All four patients were born at term and discharged home without seizures or concern of encephalopathy, but developed infantile spasms with hypsarrhythmia (or modified hypsarrhythmia) between the ages of 4-6 months.  At last follow up (ages 3-11 years), all patients were seizure-free and had severe developmental delay. In vitro experiments showed that Kv7.2 R198Q subunits shifted current activation gating to hyperpolarized potentials, indicative of gain-of-function; in neurons, Kv7.2 (n=19) and Kv7.2 R198Q (n=12) subunits similarly populated the axon initial segment (AIS), showing identical AIS/soma and AIS/dendrites ratios (p>0.05; Student’s t-test). Conclusions: The disease course similarities within our small cohort strongly suggests that the shared R198Q variant, never previously reported in neonatal-onset KCNQ2 related epilepsy, is pathogenic for IS, an infantile onset EE. The present results highlight the benefits of transnational networks and multidisciplinary-curated gene-specific databases for hastening progress in phenotypic characterization, patient stratification, and individual tailoring of therapeutic approaches in rare genetic epilepsies. Funding: The present study was supported by grants from: AES/EF Research Infrastructure Grant, The Jack Pribaz Foundation, NIH NS49119 to ECC; Telethon Foundation GGP15113 to MT; SIR 2014 RBSI1444EM to FM.