KCNQ2 epilepsy related syndromes

Saroj D Kunnakkat DO MS MPH

Epilepsy & Seizures

Updated 03.24.2025
Expires For CME 03.24.2028

KCNQ2 epilepsy related syndromes

Author: Saroj D Kunnakkat DO MS MPH

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Editor: Solomon L Moshé MD

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KCNQ2 epilepsy related syndromes

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Introduction

Overview

KCNQ2 is a gene that plays a pivotal role in the pathogenesis of a number epileptic syndromes. The spectrum of disorders is broad, ranging from KCNQ2 self-limited familial neonatal epilepsy to KCNQ2 developmental epileptic encephalopathy (09). Aside from these, other entities that do not neatly fall into these categories have been identified and implicate the role of mutations in the KCNQ2 gene.

Key points

	• KCNQ2 self-limited familial neonatal epilepsy (KCNQ2-SLFNE) represents the mildest manifestation of KCNQ2.
	• KCNQ2 developmental epileptic encephalopathy (KCNQ2-DEE and KCNQ2-NEO-DEE) is a heterogeneous entity encompassing a host of epileptic encephalopathies within which KCNQ2 mutations have been identified.

Historical note and terminology

KCNQ2 self-limited familial neonatal epilepsy was first described in the 1960s by Andreas Rett. The phenomenon, previously known as benign neonatal convulsions, was observed in a family. Children in this family would experience their first seizures around 3 days of age; these were generalized seizures and would often occur upwards of 15 to 20 times per day (20).

In 1998, the KCNQ2 gene and its resulting potassium channel abnormality were discovered. It was already known that the gene underlying benign familial neonatal seizures (now self-limited familial neonatal epilepsy) mapped to 20q13.3 (13). The developmental epileptic encephalopathy phenotype, in contrast, is a relatively recent discovery. In a 2012 analysis of 80 patients with seizures occurring early in life alongside developmental delay, eight patients (10%) had a mutation in KCNQ2 (18).

Clinical manifestations

Presentation and course

	• KCNQ2 self-limited familial neonatal epilepsy starts soon after birth, but seizures stop before the first birthday.
	• KCNQ2-DEE is a more severe form, but early on, it may be difficult to differentiate this from KCNQ2-SLFNE.

KCNQ2-SLFNE is characterized by seizures that begin within the first few days of life (typically between 2 and 8 days). These tend to remit by the child’s first birthday.

Although the role of KCNQ2 has been shown within the context of self-limited familial neonatal epilepsy (a relatively mild entity with overall good outcomes), KCNQ2-DEE is a far more severe manifestation. This entity is characterized by medically refractory seizures along with often severe developmental delay. The role of KCNQ2 in more severe forms of epilepsy is a more recent discovery (13). A 2013 paper by Weckhuysen and colleagues identified nine novel missense mutations within the KCNQ2 gene in 11 patients of an 84-patient cohort (17). From a phenotypic standpoint, the severity of their seizures varied, as did their level of cognitive impairment; one patient succumbed to what was believed to be sudden unexpected death in epilepsy.

At onset in neonates, it may be difficult to differentiate between KCNQ2-SLFNE and KCNQ2-DEE. However, for patients with KCNQ2-DEE, the interictal EEG is more likely to be abnormal, and clinically, they may experience other signs of neurologic dysfunction in tandem with their seizures (08).

KCNQ2 has been implicated in other forms of epilepsy, though the correlation is not as robust as it is for self-limited familial neonatal epilepsy and developmental epileptic encephalopathy. A case report published in 2003 noted multiple members of a family (a father and two children) whose neonatal seizures were well-controlled with phenobarbital but recurred later in infancy during attempts to wean this medication (04). One of the children later developed centro-temporal spikes at around 3 years of age. A mutation in exon 16 of the KCNQ2 gene was noted in all assessed affected members.

Prognosis and complications

The prognosis is variable and depends strongly on the syndrome that manifests as a result of mutations in KCNQ2. KCNQ2-SLFNE skews milder, with remission during infancy; other entities, however, may carry a poorer prognosis.

Management

	• Retigabine may be effective in KCNQ2 epileptic encephalopathy but carries side effects that include discoloration of the skin and retina.
	• Sodium-channel blockers have been found to be effective, along with others such as phenobarbital.

Retigabine (also known as ezogabine) is thought to exert its actions via slow-M channel modulation. Increasing hyperpolarization may help enhance its overall functioning (03). However, this promise is tempered by its side-effects, namely discoloration of the retina and skin (11). In a systematic review Kuersten and colleagues analyzed 217 subjects from 52 studies and found that phenobarbital may have particular efficacy within those with KCNQ2 mutations and a benign clinical course; for those with developmental epileptic encephalopathy, sodium-channel blockers appeared to be effective, a finding also noted in the benign group (07).

Delving further into specific mutations within the KCNQ2 gene, whether gain-of-function mutations or loss-of-function mutations, there appear to be particular mutations that respond more readily to particular pharmacologic approaches. Most mutations that contribute to the phenotypic manifestations of KCNQ2 epileptic encephalopathy are loss-of-function mutations and typically present with neonatal seizures. In a retrospective study, Millichap and colleagues looked at patients with KCNQ2 mutations across the phenotypic spectrum who were treated with ezogabine; the patients who appeared to benefit the most were not only started early but had mutations that were located at or near the ion pore-conducting domain (10). Given the side-effect profile of ezogabine, its clinical use was withdrawn by the manufacturer. Cannabidiol has been tested in an in-vitro model looking at the effects on activation of Kv7.2/7.3 channels in rat hippocampal neurons and was shown to activate these channels (19).

Gain of function mutations are less often implicated in the pathogenesis of KCNQ2, but there have been case reports where the underlying KCNQ2 gene abnormalities were specifically certain gain of function mutations (02).

Outcomes

The outcomes for patients diagnosed with a KCNQ2 epileptic encephalopathy depend strongly on the specific subset within this larger umbrella. For patients diagnosed with self-limited (familial) neonatal seizures, the outcome can be favorable; seizures often remit by around 6 months in most cases. However, KCNQ2-DEE carries a more variable and often poorer prognosis. In a retrospective study, Pisano and colleagues found the use of sodium-channel blockers, namely carbamazepine and phenytoin, to be effective in patients with KCNQ2-SLFNE and KCNQ2-DEE (11).

References

01: Barbour K, Tian N, Yozawitz EG, et al. Population-based study of rare epilepsy incidence in a US urban population. Epilepsia 2024;65(8):2341-53. PMID 38795333
02: Bayat A, Iavarone S, Miceli F, et al. Phenotypic and functional assessment of two novel KCNQ2 gain-of-function variants Y141N and G239S and effects of amitriptyline treatment. Neurotherapeutics 2024;21(1):e00296. PMID 38241158
03: Brown DA, Passmore GM. Neural KCNQ (Kv7) channels. Br J Pharmacol 2009;156(8):1185-95. PMID 19298256
04: Coppola G, Castaldo P, Miraglia del Giudice E, et al. A novel KCNQ2 K+ channel mutation in benign neonatal convulsions and centrotemporal spikes. Neurology 2003;61(1):131-4. PMID 12847176
05: Guerrini R, Conti V, Mantegazza M, Balestrini S, Galanopoulou AS, Benfenati F. Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum. Physiol Rev 2023;103(1):433-513. PMID 35951482
06: Kearney JA, Yang Y, Beyer B, et al. Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2. Hum Mol Genet 2006;15(6):1043-8. PMID 16464983
07: Kuersten M, Tacke M, Gerstl L, Hoelz H, Stülpnagel CV, Borggraefe I. Antiepileptic therapy approaches in KCNQ2 related epilepsy: a systematic review. Eur J Med Genet 2020;63(1):103628.** PMID 30771507
08: Miceli F, Millevert C, Soldovieri MV, et al. KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism. EBioMedicine 2022a;81:104130. PMID 35780567
09: Miceli F, Soldovieri MV, Weckhuysen S, Cooper E, Taglialatela M. KCNQ2-related disorders. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Updated May 19, 2022b.** PMID 20437616
10: Millichap JJ, Park KL, Tsuchida T, et al. KCNQ2 encephalopathy: features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet 2016;2(5):e96. PMID 27602407
11: Pisano T, Numis AL, Heavin SB, et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia 2015;56(5):685-91. PMID 25880994
12: Ronen GM, Rosales TO, Connolly M, Anderson VE, Leppert M. Seizure characteristics in chromosome 20 benign familial neonatal convulsions. Neurology 1993;43(7):1355-60.** PMID 8327138
13: Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 1998;18(1):25-9.** PMID 9425895
14: Snyder HE, Jain P, RamachandranNair R, Jones KC, Whitney R. Genetic advancements in infantile epileptic spasms syndrome and opportunities for precision medicine. Genes (Basel) 2024;15(3):266. PMID 38540325
15: Steinlein OK, Stoodt J, Biervert C, Janz D, Sander T. The voltage gated potassium channel KCNQ2 and idiopathic generalized epilepsy. Neuroreport 1999;10(6):1163-6. PMID 10363917
16: Symonds JD, Zuberi SM, Stewart K, et al. Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort. Brain 2019;142(8):2303-18. PMID 31302675
17: Weckhuysen S, Ivanovic V, Hendrickx R, et al. Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients. Neurology 2013;81(19):1697-703. PMID 24107868
18: Weckhuysen S, Mandelstam S, Suls A, et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol 2012;71(1):15-25. PMID 22275249
19: Zhang HB, Heckman L, Niday Z, et al. Cannabidiol activates neuronal Kv7 channels. Elife 2022;11:e73246. PMID 35179483
20: Zimprich F, Ronen GM, Stögmann W, et al. Andreas Rett and benign familial neonatal convulsions revisited. Neurology 2006;67(5):864-6. PMID 16966552
21: References especially recommended by the author or editor for general reading.

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Saroj D Kunnakkat DO MS MPH

Dr. Kunnakkat of Montefiore Medical Center has no relevant financial relationships to disclose.
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Editor

Solomon L Moshé MD

Dr. Moshé of Albert Einstein College of Medicine has no relevant financial relationships to disclose.
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Patient Profile

Age range of presentation: Typical: at or soon after birth
Sex preponderance: No sex preponderance
Heredity: Heredity may be a factor
Population groups selectively affected: No population group selectively affected
Occupation groups selectively affected: No occupation group selectively affected

ICD & OMIM codes

ICD-10: KCNQ2-related epilepsy: G40.84
ICD-11: Neonatal seizures: KB06

Epileptic encephalopathies, unspecified: 8A62.Z
OMIM: KCNQ2: 602235

BFNS: 121200

DEE7: #613720 (# used given implication of KCNQ2 in this condition)

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KCNQ2 epilepsy related syndromes

Associated Disorders

Self-limited familial neonatal epilepsy (SLFNE)
KCNQ2-DEE

Differential Diagnosis

Dravet syndrome
West syndrome
Lennox-Gastaut syndrome

Also Relevant

Epilepsy in infancy with migrating focal seizures
Infantile epileptic spasms syndrome
Pharmacological treatment of epilepsy in neonates
Self-limited (familial) infantile epilepsy
Self-limited (familial) neonatal epilepsy

Clinical Categories

Epilepsy & Seizures

KCNQ2 epilepsy related syndromes

KCNQ2 epilepsy related syndromes

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Fenfluramine

Self-limited (familial) infantile epilepsy

Jacksonian seizures

Hippocampal and parahippocampal seizures

Sleep hyperkinetic (hypermotor) epilepsy

Alcohol withdrawal seizures

Visual-sensitive epilepsies

Epilepsy surgery in children

	• The KCNQ2 gene encodes Kv7 potassium channels.
	• This gene is located on chromosome 20q13.3.

	• Testing should start with history, physical examination, labs, and imaging.
	• Genetic testing should be considered thereafter.
	• EEG findings are variable and may depend on the underlying condition.

KCNQ2 epilepsy related syndromes

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Fenfluramine

Self-limited (familial) infantile epilepsy

Jacksonian seizures

Hippocampal and parahippocampal seizures

Sleep hyperkinetic (hypermotor) epilepsy

Alcohol withdrawal seizures

Visual-sensitive epilepsies

Epilepsy surgery in children

This is an article preview.
Start a Free Account
to access the full version.