Infantile spasms and encephalopathy without preceding neonatal seizures caused by KCNQ2 R198Q, a gain‐of‐function variant
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Summary: Variants in KCNQ 2 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 KCNQ 2 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 KCNQ 2‐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 KCNQ 2 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 KCNQ 2 R198Q is a model for a new subclass of KCNQ 2 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 here
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GOF KCNQ2 DEEs include IESS associated with a recurrent GOF variant with severe outcome.
“Conversely, GOF KCNQ2 DEEs include IESS associated with a recurrent GOF variant with severe outcome 48 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [48]
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Ion currents through the voltage sensor domain of distinct families of proteins
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MLe-KCNQ2: An Artificial Intelligence Model for the Prognosis of Missense KCNQ2 Gene Variants
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Lipophilic compounds restore function to neurodevelopmental-associated KCNQ3 mutations
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In Silico Predictions of KCNQ Variant Pathogenicity in Epilepsy
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Effect of a sensing charge mutation on the deactivation of KV7.2 channels
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Personalized treatment in the epilepsies: challenges and opportunities
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Assessment of gabapentin efficacy in patients with KCNQ2-developmental epileptic encephalopathy
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Genetic Polymorphism in Febrile Seizures
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Lipophilic compounds restore wt function of neurodevelopmental-associated KCNQ3 mutationsPreprint
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- Authors
- Millichap, J. J., Miceli, F., De Maria, M., Keator, C., Joshi, N., Tran, B., Soldovieri, M. V., Ambrosino, P., Shashi, V., Mikati, M. A., Cooper, E. C., & Taglialatela, M.
- Affiliations
- Epilepsy Center and Division of Neurology Departments of Pediatrics and Neurology Ann & Robert H. Lurie Children's Hospital of Chicago Northwestern University Feinberg School of Medicine Chicago Illinois U.S.A
- University of Naples Federico II (IT)
- Department of Medicine and Health Science University of Molise Campobasso Italy
- Cook Children's Medical Center (US)
- Baylor College of Medicine (US)
- University of Molise (IT)
- Duke University (US)
- Corresponding author
- Cooper, Edward C.
- Taglialatela, Maurizio
- ORCID
- Venue
- Epilepsia
- Publisher
- Wiley
- Published
- 2016-11-09
- Volume
- 58
- Issue
- 1
- Pages
- e10-e15
- ISSN
- 0013-9580 (ISSN-L)
- 1528-1167
- PMC
- PMC5219941
- OpenAlex
- W2550390537
- Cited by
- 103
- References
- 19
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 14 · 2023: 15 · 2022: 11 · 2021: 11 · 2020: 11 · 2019: 11 · 2018: 9 · 2017: 4
- FWCI
- 7.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Epilepsia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi del Molise (submittedVersion)
- Funders
- American Epilepsy Society
- National Institutes of Health (NS49119)
- Fondazione Telethon (GGP15113)
- Ministero dell’Istruzione, dell’Università e della Ricerca (SIR 2014 RBSI1444EM)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- KCNQ2, gain-of-function mutations, infantile spasms, epileptic encephalopathy, hypsarrhythmia, developmental delay, axon initial segment, channel gating, neonatal seizures
- MeSH terms
- Animals, Arginine, Brain Diseases, Cells, Cultured, Child, Child, Preschool, Cricetulus, Glutamine, Hippocampus, Humans, Infant, Longitudinal Studies, Membrane Potentials, Models, Molecular, Mutation, Neurons, Spasms, Infantile, Transfection, CHO Cells, Rats, KCNQ2 Potassium Channel
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