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KCNQ2-Related Disorders

, PhD, , PhD, , BDS, MPH, , MD, PhD, , MD, PhD, and , MD, PhD.

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Initial Posting: ; Last Revision: September 27, 2018.

Estimated reading time: 32 minutes


Clinical characteristics.

KCNQ2-related disorders represent a continuum of overlapping neonatal epileptic phenotypes caused by a heterozygous pathogenic variant in KCNQ2. The clinical features of KCNQ2-related disorders range from KCNQ2-related benign familial neonatal epilepsy (KCNQ2-BFNE) at the mild end to KCNQ2-related neonatal epileptic encephalopathy (KCNQ2-NEE) at the severe end.

  • KCNQ2-BFNE is characterized by a wide spectrum of seizure types (tonic or apneic episodes, focal clonic activity, or autonomic changes) that start in otherwise healthy infants between the second and eighth day of life and spontaneously disappear between the first and the sixth to 12th month of life. Motor activity may be confined to one body part, migrate to other body regions, or generalize. Seizures are generally brief, lasting one to two minutes. Rarely, KCNQ2-BFNE may evolve into status epilepticus. About 10%-15% of individuals with BFNE develop epileptic seizures later in life.
  • KCNQ2-NEE is characterized by multiple daily seizures beginning in the first week of life that are mostly tonic, with associated focal motor and autonomic features. Seizures generally cease between ages nine months and four years. At onset, EEG shows a burst-suppression pattern or multifocal epileptiform activity; early brain MRI can show basal ganglia and thalamic hyperintensities that later resolve. Moderate to severe developmental impairment is present.


The diagnosis relies on the presence of characteristic clinical findings and heterozygous pathogenic variants in KCNQ2 (also known as Kv7.2), which codes for voltage-gated potassium channel subunits.


Treatment of manifestations:

  • KCNQ2-BFNE. The majority of children can be kept seizure-free by using phenobarbital (20 mg/kg as loading dose and 5 mg/kg/day as maintenance dose). In some affected individuals, seizures require other antiepileptic drugs (AEDs).
  • KCNQ2-NEE. Children have multiple daily seizures resistant at onset to phenobarbital and other common old- and new-generation AEDs, alone or in combination. Sodium channel blockers like phenytoin (PHT) or carbamazepine (CBZ) were shown to control seizures in several patients and should be considered first-line treatment.


  • KCNQ2-BFNE. EEG at age three, 12, and 24 months is appropriate. At 24 months EEG should be normal.
  • KCNQ2-NEE. EEG monitoring is highly recommended, although specific guidelines are not available.

Genetic counseling.

KCNQ2-related disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with KCNQ2-BFNE have an affected parent; however, a proband may have KCNQ2-BFNE as the result of a de novo pathogenic variant. Almost all individuals with KCNQ2-NEE have a de novo pathogenic variant. Each child of an individual with a KCNQ2-related disorder has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

GeneReview Scope

KCNQ2-Related Disorders: Included Phenotypes 1
  • Benign familial neonatal epilepsy (BFNE)
  • Neonatal epileptic encephalopathy (NEE)

For synonyms and outdated names see Nomenclature.


For other genetic causes of these phenotypes see Differential Diagnosis.


KCNQ2-related disorders represent a continuum of overlapping neonatal epileptic phenotypes ranging from KCNQ2-related benign familial neonatal epilepsy (BFNE) at the mild end to KCNQ2-related neonatal epileptic encephalopathy (NEE) at the severe end.


In KCNQ2-BFNE, all laboratory tests are normal, including brain CT and MRI.

In KCNQ2-NEE, brain MRI frequently shows bilateral or asymmetric hyperintensities in the basal ganglia, and sometimes in the thalamus; these may resolve over time. Other common findings are small frontal lobes with increased adjacent extra-axial spaces, thin corpus callosum, and decreased posterior white matter volume.

Establishing the Diagnosis

The diagnosis of a KCNQ2-related disorder is established in a proband with a characteristic history and examination when a heterozygous pathogenic variant is identified in KCNQ2 by molecular genetic testing (see Table 1).

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of KCNQ2 is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multigene panel that includes KCNQ2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes KCNQ2) fails to confirm a diagnosis in an individual with features of a KCNQ2-related disorder. Such testing may provide an unexpected or previously unconsidered diagnosis, such as mutation in another gene that causes a similar clinical presentation.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in KCNQ2-Related Disorders

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
KCNQ2Sequence analysis 3
Gene-targeted deletion/duplication analysis5
  • 20%-40% of KCNQ2-BFNE 6
  • No deletions/duplications described in individuals with KCNQ2-NEE

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


In 60% and 80% of probands with BFNE, a likely-pathogenic variant in KCNQ2 can be found (17/30 [Singh et al 2003]; 27/33 [Grinton et al 2015]). In 10/80 [Weckhuysen et al 2012] or 11/84 [Weckhuysen et al 2013] of individuals with unexplained neonatal or early-infantile seizures and psychomotor retardation with a negative family history, a pathogenic de novo KCNQ2 variant can be detected (~10% overall). This figure is higher if probands with neonatal-onset EE only are included (3/12 [Saitsu et al 2012]) or if individuals with epilepsy onset in the first three months are included (16/71 [Milh et al 2013]). It is lower (5%) if individuals with later-onset infantile seizures (West syndrome) are also included (12/239 [Kato et al 2013]).


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


In BFNE, one large duplication and several large deletions involving KCNQ2, some also involving contiguous genes, have been reported [Singh et al 1998, Heron et al 2007, Kurahashi et al 2009, Soldovieri et al 2014, Grinton et al 2015]. Deletions or duplications of KCNQ2 were found in 4/21 individuals with BFNE, benign familial neonatal-infantile seizures (BFNIS), or simplex neonatal seizures (i.e., a single occurrence in a family) in whom no coding or splice site pathogenic variants had been identified in either KCNQ2 or KCNQ3. Among families with BFNE, the detection rate was 4/9 cases [Heron et al 2007]. In the RIKEE database (www​, which contains information about KCNQ2 variants that have been published in the medical literature through December 2015, nine submicrosopic deletions are reported among 119 reported unrelated BFNE cases/pedigrees (7.6%). For information about KCNQ3 see Differential Diagnosis.

Suggestive Findings

KCNQ2-related disorders should be suspected in individuals with the following two presentations.

KCNQ2-related benign familial neonatal epilepsy (KCNQ2-BFNE) [Berg et al 2010] is characterized by the following general features:

  • Seizures starting between two and eight days after term birth and spontaneously disappearing between the first and the sixth to the 12th month of life in an otherwise healthy infant
  • Normal physical examination and laboratory tests prior to, between, and after seizures
  • No specific EEG criteria

Seizure features include the following [International League Against Epilepsy 1989, Ronen et al 1993, Engel 2001]:

  • A wide spectrum of seizure types is seen, encompassing tonic (often focal) or apneic episodes, focal clonic activity, or autonomic changes.
  • Ictal motor activity may be confined to one limb, migrate to other body regions, or generalize.
  • Seizures are generally brief, lasting one to two minutes. However, they may be very frequent and cause considerable concern, especially if the proband is the first family member being affected.
  • Infants are well between seizures, feed normally, and show normal social and motor developmental progression.
  • Rarely, seizures occur in a crescendo of activity, with a possible evolution into status epilepticus.
  • Interictal EEG may be normal, rarely showing a pattern of "theta pointu alternant."
  • Ictal EEG shows focal discharges with possible secondary generalization.

KCNQ2-related neonatal epileptic encephalopathy (KCNQ2-NEE) is characterized by the following:

  • Seizure onset occurs in the first week of life.
  • Seizures are mostly tonic, with associated focal motor and autonomic features (similar to KCNQ2-BFNE).
  • Multiple daily seizures occur at onset, with frequent seizures in the first few months to the first year of life.
  • Cessation of seizures generally occurs between age nine months and four years.
  • Encephalopathy is present from birth and persists during and after the period when seizures are uncontrolled. Subsequently, developmental impairment is moderate in about one third of individuals, and severe to profound in the remaining two thirds.
  • EEGs in the first week of life show a burst suppression pattern or multifocal epileptiform activity.
  • Over time, seizure frequency diminishes, and interictal epileptiform discharges become less frequent. EEGs after seizure freedom is achieved are normal or show mild slow background activity.

Contiguous Gene Rearrangements

In two individuals with BFNE in whom exon deletions in KCNQ2 were identified, concomitant deletions of the adjacent gene CHRNA4, encoding the cholinergic receptor, nicotinic alpha 4 subunit, have been described [Kurahashi et al 2009]. The clinical course in these individuals was that of typical BFNE, and neither had the phenotype of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), another focal epilepsy caused by pathogenic missense (but not deletion) variants in CHRNA4.

Individuals with chromosomal microdeletions at 20q13.33 were shown to have epileptic seizures mostly beginning within the neonatal period and disappearing by age four months, similar to epilepsy phenotypes of BFNE; developmental outcome was good in patients with deletion restricted to CHRNA4, KCNQ2, and COL20A1, whereas delay in developmental milestones and behavioral problems such as autistic spectrum disorder was observed in patients with a wider range of deletion [Traylor et al 2010, Pascual et al 2013, Okumura et al 2015].

Clinical Characteristics

Clinical Description

KCNQ2-related disorders include a continuum of overlapping neonatal-onset epileptic phenotypes ranging from benign familial neonatal epilepsy at the mild end to epileptic encephalopathy at the severe end.

KCNQ2-Related Benign Familial Neonatal Epilepsy (KCNQ2-BFNE)

Seizures in neonates with KCNQ2-BFNE start between age two and eight days of life and spontaneously disappear between the first and the sixth to 12th month of life in otherwise healthy infants, in a context of normal neuropsychological development and EEG recordings.

Historically, the percentage of children with KCNQ2-BFNE who experience subsequent (i.e., post-infantile) focal or generalized seizures has been thought to be in the 10%-15% range [Ronen et al 1993, Plouin & Neubauer 2012]. However, in a recent comprehensive follow-up study in which 140 individuals (27 families) were followed for up to 25 years, post-infantile seizures recurred in 40 (31%). Although the characteristics of such recurrences were varied, three common patterns emerged: simple febrile seizures (n=18; 13%), seizures in childhood (n=14; 10%), and seizures primarily in adolescence or adulthood (n=19; 14%). A few children with KCNQ2-BFNE have been noted to develop an EEG trait characterized by centrotemporal spikes (CTS) and sharp waves or benign epilepsy with centrotemporal spikes (BECT) [Coppola et al 2003, Ishii et al 2012].

KCNQ2-Related Neonatal Epileptic Encephalopathy (KCNQ2-NEE)

In rare instances, KCNQ2 pathogenic variants have been observed in families with KCNQ2-BFNE including one or more individuals who developed a therapy-resistant epileptic encephalopathy shortly after birth and a variable degree of intellectual disability by age four to five years [Alfonso et al 1997, Dedek et al 2003, Borgatti et al 2004]. In all these cases, the poor developmental outcome was not associated with neuroradiologic abnormalities suggestive of prenatal or perinatal damage. In light of more recent findings (see following), the BFNE phenotype of some family members could be explained by genetic mosaicism.

More recently, a distinct neonatal epileptic encephalopathy linked to KCNQ2 pathogenic variants has been reported in eight of 80 probands with neonatal epileptic encephalopathy, early-onset refractory seizures, and intellectual disability of unknown origin [Weckhuysen et al 2012]. In most of these affected individuals, developmental delay was associated with axial hypotonia and/or spastic quadriplegia. Most patients are severely delayed in reaching developmental milestones, are nonverbal, or only use a few words or short sentences. Some are unable to sit independently, have poor eye contact, and show little interest in their surroundings. Seizures as well as early MRI brain abnormalities (mainly occurring in the basal ganglia and thalamus) generally resolved by age three years. After this first report, additional studies have identified novel KCNQ2 variants in individuals with neonatal epileptic encephalopathy [Allen et al 2013, Carvill et al 2013, Milh et al 2013, Weckhuysen et al 2013, Allen et al 2014, Dalen Meurs-van der Schoor et al 2014, Milh et al 2015, Pisano et al 2015].

At the most severe end of the spectrum, some affected individuals have symptoms that fall within the clinical description of Ohtahara syndrome [Saitsu et al 2012, Kato et al 2013, Martin et al 2014], an early-onset age-related epileptic encephalopathy characterized by typical suppression-burst EEG pattern within the first months of life and poor outcome in terms of psychomotor development and seizure control (see Differential Diagnosis).

Other Rarer Phenotypes

Myokymia. In two families with a KCNQ2 pathogenic variant (p.Arg207Trp) neonatal seizures were later followed by peripheral nerve hyperexcitability (myokymia) [Dedek et al 2001] or myoclonus-like dyskinesia [Blumkin et al 2012]. Myokymia in the absence of neonatal seizures was described in one individual with a KCNQ2 pathogenic variant who represented a simplex case (i.e., a single occurrence in a family) [Wuttke et al 2007].

Benign familial infantile seizures (BFIS) is characterized by later onset of seizures (age ~6 months). A KCNQ2 pathogenic variant has been detected in a Chinese family with BFIS [Zhou et al 2006]. In this case, the proband also developed paroxysmal myokymic episodes.

Infantile spasms. Three children with a de novo KCNQ2 pathogenic variant who did not have neonatal seizures but onset of infantile spasms at a few months of age have been reported [Allen et al 2013, Carvill et al 2013, Weckhuysen et al 2013]. They all had concomitant intellectual disability.

Genotype-Phenotype Correlations

Given the rarity of KCNQ2-related disorders and the inter- and intrafamilial phenotypic variability, genotype-phenotype correlations are difficult to establish. Nonetheless, attempts are under way to correlate the KCNQ2 variant type with the clinical course and severity of the disease.

In general, haploinsufficiency caused by the loss of function of a single KCNQ2 allele (nonsense, splice, or frameshift variant) is the most common cause of familial KCNQ2-BFNE. Pathogenic variants so far identified in KCNQ2-NEE are all de novo missense variants, and are thought to exert more severe functional defects on potassium current function [Miceli et al 2013, Orhan et al 2014].

Individuals harboring identical recurring pathogenic variants so far appear to have broadly similar seizure and developmental outcomes, although some cases in which clinical heterogeneity appears to be associated with the same variant are also present in the literature. For example, the p.Arg213Trp KCNQ2 pathogenic variant has been reported in a severely affected individual and in a family with BFNS [Sadewa et al 2008, Milh et al 2015]. Moreover, although neurodevelopmental outcome was overall poor among individuals with KCNQ2-NEE caused by the recurrent p.Ala294Val variant, and all infants had burst-suppression on EEG, one child appeared less impaired (i.e., sat up and spoke 3 words at age 2 years). Genetic background and environmental factors such as treatment and seizure duration may further influence the phenotypic expression of the variants.

A few children with KCNQ2-NEE were born from mosaic parents (the pathogenic allele detected in blood, skin, and hair root samples ranging from 5% to 30% of cells). The neurologic development of the mosaic parents was normal, although several had neonatal seizures [Weckhuysen et al 2012, Milh et al 2015]; these findings suggest that in order to cause a persistent neurologic disease, KCNQ2 pathogenic variants with a more severe functional effect must be present in a sufficient proportion of cells.


For KCNQ2-BFNE, penetrance is incomplete, with about 77%-85% of individuals heterozygous for a pathogenic variant in KCNQ2 showing neonatal or early-infantile seizures [Plouin & Neubauer 2012, Grinton et al 2015].

Penetrance is complete for germline variants leading to KCNQ2-NEE.

No age- or sex-related differences have been reported.


The familial occurrence of neonatal seizures was first reported by Rett & Teubel [1964], who described an epileptic syndrome in which children in three generations had neonatal seizures that mostly disappeared in girls after six to eight weeks but persisted in boys throughout adolescence. The neonatal seizures were not associated with perinatal complications, such as intracranial bleeding. The term "benign" was added to the designation "familial neonatal convulsions" by Bjerre & Corelius [1968], who described a five-generation family with neonatal convulsions but normal motor and mental development, highlighting the mostly favorable outcome of the syndrome.

Subsequently it was noted that in rare instances, KCNQ2 pathogenic variants can be observed in children who develop a therapy-resistant epileptic encephalopathy shortly after birth and a variable degree of intellectual disability by age four to five years [Alfonso et al 1997, Dedek et al 2003, Borgatti et al 2004, Schmitt et al 2005]. Thus, the favorable outcome of this disorder implied by the name "benign" was questioned [Steinlein et al 2007]. More recent reports of certain KCNQ2 pathogenic variants leading to a neonatal epileptic encephalopathy with early-onset refractory seizures and intellectual disability of unknown origin have led to proposal of the name "KCNQ2 encephalopathy" [Weckhuysen et al 2012].

Because of the variable clinical phenotypes associated to pathogenic variants in KCNQ2, the authors refer to a spectrum of KCNQ2-related diseases ranging from self-limiting KCNQ2-BFNE to severe KCNQ2-NEE.


KCNQ2-related disorders comprise a large spectrum of phenotypes. Both KCNQ2-related classic BFNE and the recently described KCNQ2-NEE are rare. To date, about 100 families with KCNQ2-BFNE and about 100 individuals with KCNQ2-NEE from many different nationalities have been described in the literature. It is likely that many cases of KCNQ2-BFNE go untested and/or are not reported owing to the brief duration of symptoms and good outcome. KCNQ2-NEE is a very recently described syndrome. Therefore, at present, it is difficult to determine overall prevalence or ethnicity-dependent variability.

Differential Diagnosis

Other Causes of Benign Familial Neonatal Epilepsy (BFNE)

KCNQ3, a close homolog of KCNQ2, encodes a voltage-gated potassium channel subunit that co-assembles with the KCNQ2 protein product [Wang et al 1998, Cooper et al 2000]. KCNQ3 is a minor locus for BFNE [Charlier et al 1998]. The clinical characteristics of BFNE caused by pathogenic variants in KCNQ2 or in KCNQ3 appear indistinguishable; thus, molecular genetic testing of both genes is commonly performed when BFNE is suspected. See KCNQ3-Related Disorders.

Other genetic loci. The existence of other loci associated with BFNE cannot be excluded. Concolino et al [2002] reported a family in whom a pericentric inversion of chromosome 5 segregates with BFNE; no linkage to KCNQ2 or KCNQ3 was found in this family. Among 36 families with familial neonatal-onset seizures, three did not have pathogenic variants identified in KCNQ2 or KCNQ3, as well as in other genes associated with early-onset epilepsies (SCN2A or PRRT2); in these families, no linkage was found to any other chromosomal region [Grinton et al 2015].

Other Causes of Neonatal Epilepsy

The diagnosis of BFNE is based on the absence of any other explanation for the seizures. The reason for ordering laboratory tests is, therefore, to exclude other possible causes of the seizures.

Late hypocalcemia, vitamin B6 deficiency, hyperthyroidism, and benign sleep myoclonus should be excluded. It is also important not to miss a diagnosis of a treatable meningoencephalitis in the early stage or an intracranial hemorrhage. Both of these conditions in neonates lack the typical findings observed in older infants and children, and seizures may be the only early symptom.

The following laboratory, imaging, and instrumental studies may be helpful for the differential diagnosis:

  • Chemistries
    • Basic metabolic panel plus serum concentration of calcium, magnesium, phosphorus
    • Evaluation of alpha-AASA levels in serum and urine as a biomarker of pyridoxine (vitamin B6)-dependent seizures, a rare genetic disorder of vitamin B6 metabolism caused by pathogenic variants in ALDH7A1 and characterized by neonatal-onset seizures that are resistant to common anticonvulsants, but controlled by daily treatment with vitamin B6
      In this context it should be noted that in a recent study, a de novo KCNQ2 pathogenic variant (c.629G>A; p.Arg210His) was identified in a patient age seven years whose neonatal seizures showed a response to pyridoxine and who had a high plasma-to-CSF pyridoxal 5'-phosphate ratio but no further proof of an inborn error of vitamin B6 metabolism [Reid et al 2016].
    • Thyroid function tests, as neonatal hyperthyroid state and thyrotoxicosis may be associated with excessive tremor and jitteriness, clinical conditions that should be differentiated from seizures
  • Basic hematologic labs. CBC, prothrombin time, activated partial thromboplastin time
  • Lumbar puncture. Cerebrospinal fluid examination to exclude neonatal meningoencephalitis or occult blood
  • MRI and/or CT scan of the brain. Indicated for any individual with neonatal seizures to exclude structural lesions and intracranial hemorrhage
  • Electroencephalography. No specific EEG trait characterizes BFNE during neonatal seizures; the interictal EEG is most commonly normal (50%-70% of infants).

Later-Onset Benign Familial Seizures

Two genetic conditions that can closely resemble BFNE in rare instances are benign familial infantile seizures (BFIS), in which seizure onset is around age six months, and benign familial neonatal-infantile seizures (BFNIS), in which seizures display an intermediate age of onset between the neonatal and infantile period [Berkovic et al 2004]. Only a few KCNQ2 pathogenic variants have been detected in families with BFIS or BFNIS [Zhou et al 2006, Zara et al 2013].

Early-Infantile Epileptic Encephalopathies (EIEEs)

KCNQ2-related neonatal epileptic encephalopathy (NEE) (recently classified as early-infantile epileptic encephalopathy type 7, or EIEE 7) should be distinguished from other early-onset epileptic encephalopathies, also characterized by recurrent seizures, prominent interictal epileptiform discharges, and poor neurocognitive development. Although epileptic encephalopathies are often associated with structural brain defects or inherited metabolic disorders, pathogenic variants may also be involved in the development of epileptic encephalopathies even when no clear genetic inheritance patterns or consanguinity exist [Gürsoy & Erçal 2016]. The EIEEs are genetically very heterogeneous. Based on the genes in which pathogenic variants have been found, current classification of EIEE is as follows:

Table 2.

Genetic Heterogeneity of Early-Infantile Epileptic Encephalopathies (EIEEs)

Disease Name (OMIM/GeneReview)GeneMOI
EIEE1 (308350)ARXXL
EIEE2 (300672)CDKL5XL
EIEE3 (609304)SLC25A22AR
EIEE4 (STXBP1 Encephalopathy with Epilepsy)STXBP1AD
EIEE5 (613477)SPTAN1AD
EIEE6 (SCN1A-Related Seizure Disorders)SCN1AAD
EIEE7 (613720)KCNQ2AD
EIEE9 (300088)PCDH19XL
EIEE10 (613402)PNKPAR
EIEE11 (613721)SCN2AAD
EIEE12 (613722)PLCB1AR
EIEE13 (SCN8A-Related Epilepsy with Encephalopathy)SCN8AAD
EIEE14 (KCNT1-Related Epilepsy)KCNT1AD
EIEE15 (615006)ST3GAL3AR
EIEE16 (TBC1D24-Related Disorders)TBC1D24AR
EIEE17 (615473)GNAO1AD
EIEE18 (615476)SZT2AR
EIEE19 (615744)GABRA1AD
EIEE20 (300868)PIGAXL
EIEE21 (615833)NECAP1AR
EIEE22 (300896)SLC35A2XL
EIEE23 (615859)DOCK7AR
EIEE24 (615871)HCN1AD
EIEE25 (615905)SLC13A5AR
EIEE26 (615056)KCNB1AD
EIEE27 (GRIN2B-Related Neurodevelopmental Disorder)GRIN2BAD
EIEE28 (616211)WWOXAR
EIEE29 (616339)AARS1AR
EIEE30 (616341)SIK1AD
EIEE31 (616346)DNM1AD
EIEE32 (616366)KCNA2AD
EIEE33 (616409)EEF1A2AD
EIEE34 (SLC12A5-Related Epilepsy of Infancy with Migrating Focal Seizures)SLC12A5AR
EIEE35 (616647)ITPAAR

AD = autodomal dominant; AR = autosomal recessive; EIEE = early-infantile epileptic encephalopathy; MOI = mode of inheritance; XL = X-linked

Several of these EIEEs can have neonatal onset of seizures, including those associated with pathogenic variants in ARX, SLC25A22, CDKL5, STXBP1, PLCB1, SCN2A, KCNT1, and SLC13A5. Some specific clinical features can point toward a certain gene other than KCNQ2, such as the presence of prominent movement disorders in ARX- and SCN2A-related EIEE [Howell et al 2015], a hypermotor-tonic-spasm seizure phenotype in girls with pathogenic CDKL5 variants [Klein et al 2011], or convulsive seizures and hypodontia in SLC13A5-related EIEE [Hardies et al 2015]. Also, unlike many EIEEs, those caused by KCNQ2 pathogenic variants are characterized by decreasing frequency of seizures over the first few months or years of life.

Ohtahara syndrome is the most severe and the earliest developing age-related epileptic encephalopathy, characterized by tonic seizures occurring within the first three months of life, often within the first two weeks. Seizures that can be either generalized or lateralized may occur singly or in clusters, and are independent of the sleep cycle. The EEG in individuals with Ohtahara syndrome typically shows bursts of high-amplitude spikes and polyspikes that alternate at a regular rate with periods of electric suppression (suppression-burst EEG pattern). Psychomotor development and prognosis are generally very poor. Clinical features of Ohtahara syndrome can be caused by pathogenic variants in several genes, including ARX (EIEE1), CDKL5 (EIEE2), SLC25A22 (EIEE3), STXBP1 (EIEE4), and SCN2A (EIEE11) [Mastrangelo & Leuzzi 2012, Pavone et al 2012, Mastrangelo 2015]. Since its description, several individuals diagnosed with Ohtahara syndrome have been found to carry pathogenic variants in KCNQ2 (EIEE7).

Mosaic chromosome 20 ring [r(20)] is a chromosomal disorder that has been associated with a rare syndrome, consisting of refractory epilepsy with non-convulsive status epilepticus (NCSE) and cognitive problems [Inoue et al 1997].

FISH analyses have not shown deletions of the telomeric and subtelomeric chromosome 20 regions and, more particularly, no deletion of CHRNA4 or KCNQ2 [Zou et al 2006, Elghezal et al 2007]. Although differential diagnosis is rather straightforward because of the later (non-neonatal) onset of seizures in r(20), the direct physical link between distal 20p and 20q segments in the ring structure may disturb the correct expression or the regulation of genes located near the telomeric regions, including subtelomeric CHRNA4 and KCNQ2 [Giardino et al 2010].


Evaluations Following Initial Diagnosis

KCNQ2-related disorders represent a broad prognostic spectrum, and evaluation following a positive KCNQ2 genetic test differs depending on severity of the phenotype.

Individuals with benign familial neonatal epilepsy (BFNE)

  • In-depth neurologic examination
  • Developmental evaluation

Individuals with neonatal epileptic encephalopathy (NEE)

  • Video EEG monitoring including sleep phase to obtain information on presence of seizures. A burst suppression EEG pattern might only be seen during sleep.
  • Cognitive and behavioral neuropsychological testing
  • Assessment of digestive and other non-neurologic comorbidities

All individuals with a KCNQ2-related disorder. Consultation with a clinical geneticist and/or genetic counselor is also recommended.

Treatment of Manifestations

KCNQ2-BFNE. Seizures in individuals with BFNE are generally controlled with conventional antiepileptic treatment. Phenobarbital and phenytoin (loading doses of 15-20 mg/kg; maintenance doses of 3-4 mg/kg for both agents) [Painter et al 1981] are the antiepileptic drugs (AEDs) most commonly used to treat neonatal seizures.

Because of concerns over the suboptimal effectiveness and safety of phenytoin and phenobarbital, other anticonvulsants, such as levetiracetam and topiramate, are often used (off-label and despite limited data) in neonates with refractory seizures [Tulloch et al 2012]. Refractory seizures are uncommon in KCNQ2-related BFNE.

KCNQ2-NEE. Children with KCNQ2-related neonatal epileptic encephalopathy generally present with tonic seizures accompanied by motor and autonomic features, similar to seizures in KCNQ2-BFNE. However, individuals with KCNQ2-NEE clearly differ from those with KCNQ2-BFNE as to seizure response. Although seizure response to any of the AEDs has been described in isolated patients, many patients at onset show multiple daily seizures resistant to multiple common old- and new-generation AEDs, alone or in combination. Seizures then tend to gradually decrease by age nine months to four years [Weckhuysen et al 2012].

A favorable response to drugs acting on voltage-gated sodium channels has been suggested in several studies [Kato et al 2013, Weckhuysen et al 2013, Numis et al 2014, Pisano et al 2015]. It has been suggested that early effective treatment reduces cognitive disability [Pisano et al 2015]; however, it remains a matter of debate whether early control of seizures translates to better neuropsychological outcome.

VGB or ACTH therapy can be tried for treatment of infantile spasms that can occur during the course of the disease [Dedek et al 2003, Borgatti et al 2004, Serino et al 2013].

Management should further focus on the optimization of the patient's functional and communication skills. A multidisciplinary team approach including physiotherapists, speech therapists, and behavioral therapists is best suited to addressing the individual's needs. Augmentative communication techniques can be valuable for many patients.

Prevention of Secondary Complications

As seizure frequency tends to decrease with age, the option to taper and eventually stop AED after a sufficient seizure-free period should be considered in order to prevent complications of long-term AED use. Some children may require lifelong antiepileptic treatment.


KCNQ2-BFNE. EEG at age three, 12, and 24 months is appropriate. The EEG at 24 months should be normal.

KCNQ2-NEE. Video-EEG monitoring is appropriate when new or different seizure types are suspected.

Serial neuropsychological evaluation of neurologic, cognitive, and behavioral problems is advised.

Regular follow up by a multidisciplinary team with particular attention to nutritional intake, gastrointestinal function, mobility, and communication skills is recommended.

Agents/Circumstances to Avoid

In patients with known gain-of-function pathogenic variants in KCNQ2, the use of the potassium channel opener retigabine/ezogabine may be contraindicated.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The pregnancy management of a woman with a KCNQ2 pathogenic variant and epilepsy does not differ from that of any other pregnant woman with a seizure disorder.

A fetus with a KCNQ2 pathogenic variant may have neonatal seizures in the first few days of life. Therefore, a woman who is carrying a fetus at risk of inheriting a KCNQ2-related disorder should consider delivering in a hospital with a neonatal intensive care unit.

Therapies Under Investigation

A recent report described a positive effect of vitamin B6 on seizures in a few patients with KCNQ2-NEE [Reid et al 2016], but further studies are needed to confirm the antiepileptic effect of pyridoxine in the absence of an inherited disorder of vitamin B6 metabolism.

The selective neuronal KCNQ potassium channel opener retigabine/ezogabine, an AED introduced in 2013 as adjunctive treatment of partial epilepsy in adults [Porter et al 2012], may represent a targeted therapy for KCNQ2-NEE. However, the discovery of additional side effects in the early post-marketing (blue discoloration of skin and retina) raise concerns about its use in children. Although a good effect on seizures was described in one patient [Weckhuysen et al 2013], additional experience has not yet been reported. Furthermore, given existing in vitro evidence that some variants may lead to a gain of function, the use of retigabine/ezogabine may theoretically even be contraindicated in some patients. Further studies are needed to address whether early use of the drug in specific patient groups is effective.

Search Clinical in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

KCNQ2-related disorders are expressed in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents: if a parent of the proband has a KCNQ2 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant and being affected is 50%.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for a KCNQ2-related disorder because of the possibility of reduced penetrance or somatic/gonadal mosaicism in a parent.

Offspring of a proband

  • Each child of an individual with KCNQ2-BFNE has a 50% chance of inheriting the pathogenic variant.
  • Given the severity of the disease course, individuals with KCNQ2-NEE rarely reproduce.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected or has the KCNQ2 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals and young adults who are affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once a KCNQ2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • KCNQ2 Cure Alliance
    3700 Quebec Street
    Unit 100-118
    Denver CO 80207
    Phone: 303-887-9532
  • The Jack Pribaz Foundation
    PO Box 813
    Wheaton IL 60187
    Phone: 708-308-1440
  • American Epilepsy Society (AES)
  • Canadian Epilepsy Alliance
    Phone: 1-866-EPILEPSY (1-866-374-5377)
  • Epilepsy Foundation
    8301 Professional Place East
    Suite 200
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
  • The RIKEE Project (Rational Intervention for KCNQ2/3 Epileptic Encephalopathy) Patient Registry
    Phone: 713-798-3464
    Fax: 713-798-3455

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

KCNQ2-Related Disorders: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for KCNQ2-Related Disorders (View All in OMIM)


Molecular Pathogenesis

The KCNQ potassium channel gene subfamily consists of five members (KCNQ1-5), each encoding a subunit of a voltage-gated potassium channel. Each subunit shows distinct tissue distribution and subcellular localization, as well as biophysical, pharmacologic, and pathophysiologic properties [Miceli et al 2008, Soldovieri et al 2011].

KCNQ subunits, similarly to other voltage-gated potassium channel subunits, include six transmembrane domains, with cytoplasmic N-terminal (short) and C-terminal (longer) regions. In neurons, KCNQ2, KCNQ3, KCNQ4, and KCNQ5 subunits (either as homomultimers or heteromultimers) represent the molecular basis of the M-current (IKM), a K+-selective, non-inactivating, and slowly activating/deactivating current [Brown & Adams 1980, Wang et al 1998], showing a critical role in spike-frequency adaptation and neuronal excitability control.

In addition to KCNQ2, other KCNQ genes have a role in human genetic disease. In humans, pathogenic variants in KCNQ1 are responsible for one form of long QT syndrome (LQTS-1) [Wang et al 1996], as well as for familial atrial fibrillation [Chen et al 2003] and the short QT syndrome [Bellocq et al 2004]. Pathogenic variants in KCNQ4, expressed mainly in the cochlea and central auditory pathways, cause a rare form of nonsyndromic autosomal dominant hearing loss (DFNA2) [Kubisch et al 1999]. Finally, variants in KCNQ3 are rare causes of BFNE [Charlier et al 1998].

Gene structure. At least five transcript variants have been described for KCNQ2.

The transcript variant 1 (NM_172107.2) encodes the longest isoform, isoform a, consisting of 3,251 bp and 17 exons.

Transcript variants 2, 3, and 4 (NM_172106.1, NM_004518.4, and NM_172108.3, respectively), encode isoforms (b, c, and d, respectively) that are shorter than isoform a:

  • Transcript variant 2 lacks an in-frame exon compared to variant 1 and the encoded isoform b lacks the amino-acidic stretch from Lys417 to Ser434.
  • Transcript variant 3 lacks one more in-frame exon compared to variant 2, resulting in a shorter isoform (c) without amino acids Lys417-Ser434 and Ser373-Ser382. This variant shows a different 3'-UTR.
  • Isoform d is encoded by transcript variant 4, which lacks two in-frame exons, resulting in a protein product without Lys417-Ser446 and the single residue Glu509.

Transcript variant 5 (NM_172109.1), the shortest one, encodes a truncated isoform (isoform e) that shows a distinct C-terminus. In fact, it uses a different splicing site in the coding region, resulting in a frameshift after the Tyr375 residue. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The first pathogenic variants in KCNQ2-related disorders were described in 1998 [Biervert et al 1998, Singh et al 1998]. Table 3 lists pathogenic variants discussed in this GeneReview.

The spectrum of pathogenic variants causing KCNQ2-related disorders varies by disorder:

  • KCNQ2-BFNE. Pathogenic variants include missense, splice, stop, and frameshift variants as well as exon and whole-gene deletions; variants occur throughout the gene, leading to sequence changes distributed throughout the protein.
  • KCNQ2-NEE. Pathogenic variants are all missense and cluster in four functionally important protein domains: the voltage sensor, the pore, the C-terminus proximal region (important for modulation by second messengers), and the calmodulin-binding B helix region.

Table 3.

KCNQ2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.

Normal gene product. KCNQ2 (also known as Kv7.2) encodes for voltage-gated potassium channel subunits that are mainly (though not exclusively) expressed in the nervous system. KCNQ2 subunits form heteromultimeric channels with homologous subunits encoded by other KCNQ members expressed in the brain. Heterotetrameric channels formed by KCNQ2 and KCNQ3 subunits are believed to play a major role in mediating the so-called "M-current (IKM)," a slowly activating, non-inactivating potassium conductance that inhibits neuronal excitability. Suppression of IKM on activation of G-protein-coupled receptors (including muscarinic receptors, hence the term "M-current") increases neuronal excitability.

Abnormal gene product. Missense variants identified in BFNE lead to a 25%-50% reduction of the potassium current [Schroeder et al 1998, Singh et al 2003, Soldovieri et al 2006]. Functional studies suggest that in most cases a decrease of IKM of only 25% is sufficient to cause BFNE, arguing in favor of haploinsufficiency as the primary pathogenic mechanism for BFNE.

Various molecular mechanisms appear responsible for the mutation-induced current decrease, including a reduced number of functional channels in the plasma membrane, changes in the subcellular targeting of the channels [Abidi et al 2015], an altered regulation of their function by associated proteins (e.g., calmodulin, Ankirin-G, syntaxin-1A), and a reduced sensitivity to changes in membrane potential by correctly assembled channels [Dedek et al 2001, Castaldo et al 2002, Miceli et al 2013, Ambrosino et al 2015].

More severe consequences (often with dominant-negative effects) on channel function and/or subcellular localization have been recently associated with pathogenic variants causing KCNQ2-NEE, suggesting that clinical disease severity may be related to the extent of functional K+ channel impairment [Miceli et al 2013, Orhan et al 2014, Abidi et al 2015]. In fact, in comparative studies evaluating two different variants affecting the same residue in the KCNQ2 S4 domain (p.Arg213Trp, found in KCNQ2-BFNE and p.Arg213Gln, found in KCNQ2-NEE) [Sadewa et al 2008, Weckhuysen et al 2012], the NEE-associated p.Arg213Gln pathogenic variant was found to cause more abnormal functional changes than the BFNE-associated p.Arg213Trp pathogenic variant. In addition, while a recurrent KCNQ2 variant causing KCNQ2-NEE (p.Ala294Val) diminished the axonal targeting of KCNQ channels, another variant affecting the same residue but found in a family with KCNQ2-BFNE (p.Ala294Gly) failed to affect channel localization to the axon initial segment [Abidi et al 2015].

More recently, three KCNQ2-NEE-causing pathogenic variants have been shown to cause a stabilization of the activated stated of the channel, thereby producing a gain-of-function effect, which is opposite to the loss-of-function effects produced by previously studied pathogenic variants [Miceli et al 2015]. Whether distinct clinical features can be associated with these gain-of-function variants is currently under investigation.


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Chapter Notes


MT acknowledges Telethon (GGP15113) for supporting studies in his lab throughout the years. FM and MVS are supported by postdoctoral fellowships from the Fondazione Umberto Veronesi and the Italian Society or Pharmacology, respectively. NJ and ECC are supported by NIH NS49119, CURE, and the Jack Pribaz Foundation. SW is supported by the French program "Investissements d'avenir" (ANR-10-IAIHU-06). The collaboration of patients and their families is also highly appreciated.

Author History

Giulia Bellini, PhD; Second University of Naples (2009-2016)
Edward Cooper, MD, PhD (2016-present)
Giangennaro Coppola, MD; University of Salerno (2013-2016)
Nishtha Joshi, PhD (2016-present)
Francesco Miceli, PhD (2009-present)
Emanuele Miraglia del Giudice, MD; Second University of Naples (2009-2016)
Antonio Pascotto, MD; Second University of Naples (2009-2013)
Maria Virginia Soldovieri, PhD (2009-present)
Maurizio Taglialatela, MD, PhD (2005-present)
Sarah Weckhuysen, MD, PhD (2016-present)

Revision History

  • 27 September 2018 (aa) Revision: removed linkaway Table 4
  • 31 March 2016 (ha) Comprehensive update posted live
  • 11 April 2013 (me) Comprehensive update posted live
  • 4 August 2011 (cd) Revision: deletion/duplication analysis available clinically for KCNQ2 and KCNQ3
  • 27 April 2010 (me) Review posted live
  • 4 December 2009 (mt) Initial submission
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