期刊
EPILEPSIA
卷 58, 期 1, 页码 e10-e15出版社
WILEY
DOI: 10.1111/epi.13601
关键词
Potassium channels; Gene variants; Genotype-phenotype; Epileptic encephalopathy; retigabine; KCNQ2; axon initial segment
资金
- American Epilepsy Society/Epilepsy Foundation Research Infrastructure program
- Jack Pribaz Foundation
- National Institutes of Health (NIH) [NS49119]
- Telethon Foundation [GGP15113]
- Ministry of Education, University and Research Scientific Independence for young Researchers (SIR) grant [SIR 2014 RBSI1444EM]
Variants in KCNQ2 encoding for K(v)7.2 neuronal K+ channel subunits lead to a spectrum of neonatal-onset epilepsies, ranging from self-limiting forms to severe epileptic encephalopathy. Most KCNQ2 pathogenic variants cause loss-of-function, whereas few increase channel activity (gain-of-function). We herein provide evidence for a new phenotypic and functional profile in KCNQ2-related epilepsy: infantile spasms without prior neonatal seizures associated with a gain-of-function gene variant. With use of an international registry, we identified four unrelated patients with the same de novo heterozygous KCNQ2 c.593G>A, p.Arg198Gln (R198Q) variant. All 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 and 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, K(v)7.2 and K(v)7.2 R198Q subunits similarly populated the axon initial segment, suggesting that gating changes rather than altered subcellular distribution contribute to disease molecular pathogenesis. We conclude that KCNQ2 R198Q is a model for a new subclass of KCNQ2 variants causing infantile spasms and encephalopathy, without preceding neonatal seizures. A PowerPoint slide summarizing this article is available for download in the Supporting Information section
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