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KCNQ2-Related Disorders

, PhD, , PhD, , PhD, , MD, , MD, and , MD, PhD.

Author Information
, PhD
Department of Experimental Medicine
Second University of Naples
Naples, Italy
, PhD
Division of Pharmacology
Department of Neuroscience
University of Naples Federico II
Naples, Italy
, PhD
Department of Medicine and Health Science
University of Molise
Campobasso, Italy
, MD
Department of Women, Children, and General and Specialized Surgery
Second University of Naples
Naples, Italy
, MD
Chair, Child Neuropsychiatry
University of Salerno
Salerno, Italy
, MD, PhD
Department of Medicine and Health Science
University of Molise
Campobasso, Italy
Division of Pharmacology
Department of Neuroscience
University of Naples Federico II
Naples, Italy
; ti.lominu@aletalailgat.m

Initial Posting: ; Last Update: April 11, 2013.

Summary

Disease characteristics. KCNQ2-related disorders represent a continuum of overlapping neonatal epileptic phenotypes caused by a heterozygous mutation 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 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 BFNS 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 motor and autonomic features. Seizures cease between ages nine months and four years. At onset, EEG shows a burst-suppression pattern or multifocal epileptiform activity; early brain MRI shows basal ganglia and thalamic hyperintensities that later resolved. Most affected individuals are profoundly intellectually impaired and have axial hypotonia and/or spastic quadriplegia.

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

Management. Treatment of manifestations:

  • KCNQ2-BFNE: The majority of children can be kept seizure-free by using phenobarbital (20 mg/kg-1 as loading dose and 5 mg/kg-1/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. ACTH therapy can be tried in critical periods in the disease course.

Surveillance:

  • KCNQ2-BFNE: EEG at age three, 12, and 24 months is appropriate. The EEG at 24 months 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 a KCNQ2-related disorder have an affected parent; however, a proband may have a KCNQ2-related disorder as the result of de novo mutation. Each child of an individual with a KCNQ2-related disorder has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.

GeneReview Scope

KCNQ2-Related Disorders: Included Disorders
  • KCNQ2-related benign familial neonatal epilepsy
  • KCNQ2-related neonatal epileptic encephalopathy

For synonyms and outdated names see Nomenclature.

Diagnosis

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

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

  • Seizures starting between age two and eight days of life 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 or apneic episodes, focal clonic activity, or autonomic changes.
  • 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.
  • Infants are well between seizures and feed normally.
  • 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 motor and autonomic features (similar to KCNQ2-BFNE).
  • Multiple daily seizures at onset, with frequent seizures in the first few months to the first year of life.
  • Cessation of seizures occurs between age nine months and four years.
  • Most affected individuals are profoundly intellectually impaired and have axial hypotonia and/or spastic quadriplegia.
  • EEGs in the first week of life show a burst suppression pattern, evolving into multifocal epileptiform activity.
  • Over time, seizure frequency diminishes, epileptiform activity becomes less frequent, and EEGs after seizure freedom are normal or show mild slow background activity.

Testing

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.

Molecular Genetic Testing

Gene. KCNQ2 (also known as Kv7.2), which encodes for voltage-gated potassium channel subunits, is the only gene in which mutations cause KCNQ2-related disorders.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in KCNQ2-Related Disorders

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
KCNQ2Sequence analysis 4Sequence variants>60%?; figure uncertain because of the small number of families affected 5
Deletion/duplication analysis 6Multiexonic deletions/duplications and contiguous-gene deletions 5, 721%-44% of individuals with neonatal- or early-infantile onset seizures with no identifiable coding or splice site mutations in KCNQ2

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. 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]. Submicroscopic deletions or duplications of KCNQ2 were found in four of 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 mutations had been identified in either KCNQ2 or KCNQ3. Among those families with BFNE, the detection rate was 4/9 cases [Heron et al 2007]. For information about KCNQ3 see Differential Diagnosis.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. Extent of deletion detected may vary by method and by laboratory.These panels vary by methods used, the genes included and over time; thus, the ability of a panel to detect a causative mutation or mutations in any given individual with an epileptic encephalopathy and/or benign familial neonatal seizures also varies. In addition, a panel may not include a specific gene of interest.

Testing Strategy

To confirm/establish the diagnosis in a proband. In an individual who has clinical features consistent with a KCNQ2-related disorder, molecular genetic testing may confirm the diagnosis.

  • Single gene testing. One strategy for molecular diagnosis of a proband suspected of having a KCNQ2-related disorder is sequence analysis of KCNQ2. If no mutation is identified by sequence analysis, deletion/duplication testing may be indicated.
  • Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having a KCNQ2-related disorder is use of a multi-gene panel that includes KCNQ2 and other genes of interest. See Differential Diagnosis.
    Note: Panels vary by methods used, by genes included, and over time; thus, the ability of a panel to detect a causative mutation or mutations in any given individual with an epileptic encephalopathy and/or benign familial neonatal seizures also varies. In addition, a panel may not include a specific gene of interest.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Contiguous Gene Rearrangements

In two BFNE cases in which multiple exonic 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 courses of individuals with deletions of both KCNQ2 and CHRNA4 were those of typical BFNE, and none had the phenotype of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), another focal epilepsy caused by mutations in CHRNA4.

Clinical Description

Natural History

KCNQ2-related disorders represent a continuum of overlapping neonatal 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 mostly normal neuropsychological development and EEG recordings.

A small percentage of children with KCNQ2-BFNE (10%-15%) may develop focal or generalized idiopathic epilepsy with a variable age of onset and duration [Ronen et al 1993]. In particular, during early childhood, children with KCNQ2-BFNE may 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]. Although the age-dependent CTS trait seems to segregate independently from KCNQ2 [Neubauer et al 1997], the presence of a KCNQ2 mutation may anticipate its appearance [Coppola et al 2003].

KCNQ2-related neonatal epileptic encephalopathy (KCNQ2-NEE). In rare instances, KCNQ2 mutations have been observed in children with KCNQ2-BFNE 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]. In all these cases, the poor developmental outcome was not associated with neuroradiologic abnormalities suggestive of prenatal or perinatal damage.

More recently, a distinct neonatal epileptic encephalopathy linked to KCNQ2 mutations 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, psychomotor retardation was associated with axial hypotonia and/or spastic quadriplegia. Seizures as well as early MRI brain abnormalities (mainly occurring in the basal ganglia and thalamus) generally resolved by age three years.

At the most severe end of the spectrum, some affected individuals have symptoms that fall within the clinical description of Ohtahara syndrome, 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).

Genotype-Phenotype Correlations

KCNQ2 mutations are associated with different phenotypes including classic KCNQ2-BFNE, myokymia, peripheral nerve excitability, and intellectual disability. Given the rarity of KCNQ2-related disorders and the inter- and intra-familial phenotypic variability, genotype-phenotype correlations are quite uncertain.

KCNQ2-BFNE caused by a complete truncation of the KCNQ2 C-terminus (p.Gln323Ter) or by the c.2127delT frameshift resulting in a long stretch of substituted amino acids within the same region are associated with centrotemporal spikes (CTS) or with rolandic epilepsy (BECT) [Singh et al 1998, Coppola et al 2003, Ishii et al 2009, Ishii et al 2012]. In contrast, KCNQ2-BFNE caused by mutations leading to more dramatic functional consequences (e.g., a complete mutation-induced loss of channel function) may be responsible for more serious KCNQ2-BFNE-associated clinical phenotypes, such as mild intellectual disability and West syndrome [Bassi et al 2005], or delayed age of seizure remission [Tang et al 2004].

More recently, two mutations affecting the same positively charged residue in the voltage-sensing S4 domain of KCNQ2 have been found in children with either KCNQ2-BFNE (p.Arg213Trp) [Sadewa et al 2008] or with KCNQ2-NEE (p.Arg213Gln) [Weckhuysen et al 2012]. Functional and modeling studies revealed that the NEE-associated p.Arg213Gln mutation prompted more dramatic functional changes when compared to the BFNS-associated p.Arg213Trp mutation, suggesting that the clinical disease severity may be related to the extent of mutation-induced functional K+ channel impairment [Miceli et al 2013].

Penetrance

Penetrance is incomplete (0.8-0.85).

Anticipation

Anticipation has not been observed.

Nomenclature

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 and 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 mutations 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 recently, KCNQ2 mutations have been reported in probands with neonatal epileptic encephalopathy, early-onset refractory seizures, and intellectual disability of unknown origin, leading to proposal of the name KCNQ2 encephalopathy [Weckhuysen et al 2012].

Prevalence

KCNQ2-related disorders comprise a large spectrum of phenotypes. Both KCNQ2-related classic BFNE and the recently described KCNQ2-NEE are rare. About 80 families with KCNQ2-BFNE and only 11 families with KCNQ2-NEE from many different nationalities have been identified so far; thus, it is difficult to determine prevalence or possible ethnicity-dependent variability.

Differential Diagnosis

Multi-gene panels may include testing for a number of the genes associated with disorders discussed in this section.

Other causes of benign familial neonatal epilepsy (BFNE). KCNQ3 (also known as Kv7.3), which also encodes for voltage-gated potassium channel subunits, is a minor locus for BFNE [Charlier et al 1998]. The clinical characteristics of BFNE caused by mutations in KCNQ2 or in KCNQ3 do not appear to differ; thus, mutational screening of both genes is commonly performed when BFNE is suspected. See KCNQ3-Related Disorders.

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 benign familial neonatal convulsions; no linkage to KCNQ2 or KCNQ3 was found in this family.

The diagnosis of BFNE requires that no other explanation exists for the seizures. The reason for ordering laboratory tests is, therefore, to exclude other possible causes for the seizures.

Late hypocalcemia, subarachnoid hemorrhage, certain meningitides, and benign sleep myoclonus should be excluded.

It is also important not to miss a diagnosis of a treatable meningoencephalitis in the early stages or 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. In addition, vitamin B6 plasma concentrations should be evaluated; in fact, pyridoxine (vitamin B6)-dependent seizures is a rare disorder characterized by neonatal-onset seizures that are resistant to common anticonvulsants, but controlled by daily treatment with vitamin B6. Thyroid function tests are also suggested as neonatal hyperthyroid state and thyrotoxicosis may be associated with excessive tremor and jitteriness, clinical conditions which 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).

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].

Epileptic encephalopathies. KCNQ2-related neonatal epileptic encephalopathy should be mainly distinguished from early epileptic syndromes linked to mutations in the following genes: aristaless related homeobox (ARX; in males), cyclin-dependent kinase-like 5 (CDKL5; in females), syntaxin binding protein 1 (STXBP1), DNA polymerase gamma-1 (POLG), and solute carrier family 25 member 22 (SLC25A22). All of these conditions may show tonic fits and focal seizures with a suppression-burst pattern in the early developmental stages combined with psychomotor/mental delay and cerebral palsy as the affected individual ages. Unlike most infantile-onset epileptic encephalopathies, those caused by KCNQ2 mutations are characterized by a diminishing seizure frequency over the first few years of life.

Ohtahara syndrome is a clinical description given to the most severe and the earliest developing 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. Clinical features of Ohtahara syndrome can be caused by mutations in several genes, including aristaless-related homeobox (ARX) on chromosome Xp22.13. In twelve individuals with clinical features of Ohtahara syndrome, three KCNQ2 mutations have been recently identified [Saitsu et al 2012].

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

To date FISH analyses indicated no deletions of the telomeric and subtelomeric chromosome 20 regions or deletion of CHRNA4 or KCNQ2 [Zou et al 2006, Elghezal et al 2007]. Nevertheless 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].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

In an individual diagnosed with a KCNQ2-related disorder an in-depth neurologic examination is recommended. Medical genetics consultation is also recommended.

Treatment of Manifestations

KCNQ2-BFNE. The majority of individuals with KCNQ2-BFNE can be kept seizure-free by using phenobarbital (20 mg/kg-1 as loading dose and 5 mg/kg-1/day as maintenance dose).

In some affected individuals, seizures require other antiepileptic drugs (AEDs) such as carbamazepine (CBZ), valproic acid (VPA), clonazepam (CNZ), midazolam (MDZ), phenytoin (PHE), or vigabatrin (VGB). In two individuals with KCNQ2-BFNE and seizures resistant to most common AEDs, therapy with ACTH was attempted [Dedek et al 2003, Borgatti et al 2004].

Encephalopathy. Children with KCNQ2-related encephalopathy generally present with tonic seizures accompanied by motor and autonomic features, similar to seizures in KCNQ2-BFNE. However, individuals with KCNQ2-NEE appear clearly different from those with KCNQ2-BFNE as to seizure response, showing multiple daily seizures resistant at onset to phenobarbital and to other common old- and new-generation AEDs, alone or in combination. VPA, VGB, or CNZ or phenytoin (PHE) may be effective in some cases. Seizures tend to gradually decrease by age nine months to four years [Weckhuysen et al 2012]. ACTH therapy can be tried in critical periods in the course of the disease [Dedek et al 2003, Borgatti et al 2004].

Prevention of Secondary Complications

The potential complications of the disease treatment are those related to AED use.

Surveillance

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

KCNQ2-NEE. EEG monitoring is highly recommended, although specific guidelines for the treatment and surveillance of seizures in the milder and more severe phenotypes linked to KCNQ2 mutations are not available.

Agents/Circumstances to Avoid

KCNQ2-BFNE. In KCNQ2-related disorders with a benign course, anticonvulsant drugs like phenobarbital should be avoided for the treatment of neonatal seizures. In children who develop focal or generalized idiopathic epilepsies such as BECTS, childhood absence, or primary generalized tonic-clonic seizures, the drug therapy is the same as for individuals without KCNQ2 mutations.

KCNQ2-NEE. There are no specific treatments/medications that should be avoided or limited because they exacerbate disease manifestations.

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 mutation and epilepsy does not differ from that of any other pregnant woman with a seizure disorder.

A fetus with a KCNQ2 mutation may have neonatal seizures in the first few days of life. Therefore, a mother who has a fetus at risk of inheriting a KCNQ2-related disorder should consider delivering in a hospital with a neonatal care unit.

Therapies Under Investigation

Seizures in KCNQ2-BFNE are generally controlled with conventional antiepileptic treatment.

Retigabine is a novel anticonvulsant which selectively enhances the function of potassium channels formed by neuronal Kv7 subunits, and is currently used as an adjunctive therapy in adult individuals with partial-onset seizures [Porter et al 2012]. Flupirtine, a structural analogue of retigabine which also activates channels formed by neuronal Kv7 subunits, has been shown to be effective in animal models of neonatal convulsion [Raol et al 2009]. There are currently no data available on the clinical efficacy of this drug for the treatment of seizures in KCNQ2-related disorders.

Search Clinical Trials.gov 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, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with BFNE have an affected parent; three cases caused by de novo mutation have also been described [Sadewa et al 2008, Ishii et al 2009, Miceli et al 2009].
  • By contrast, 10/11 individuals affected with KCNQ2-related epileptic encephalopathy had de novo mutation; only one of these individuals inherited the mutation from a mosaic parent with a milder phenotype.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are: germline mosaicism in a parent or de novo mutation. To date one case of germline mosaicism has been reported [Sadewa et al 2008].
  • Recommendations for the evaluation of parents of a proband with a KCNQ2 mutation include molecular genetic testing. Detection of the same mutation found in the proband identifies an affected parent who was previously undiagnosed (because of a milder phenotypic presentation). Therefore, an apparently negative family history cannot be confirmed until appropriate genetic evaluations have been performed.

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 disease-causing mutation, the risk to the sibs of inheriting the mutation and being affected is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband may be low, although still significant because of the possibility of reduced penetrance in a parent or of a germline mutation occurring in a parent.

Offspring of a proband. The offspring of an individual with a KCNQ2-related disorder have a 50% chance of inheriting the mutation.

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 a disease-causing mutation, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or has clinical evidence of the disorder, it is likely that the proband has de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or 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 young adults who are affected or at risk.

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

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).The high inter- and intrafamilial phenotypic variability and the lack of clear-cut genotype-phenotype correlations make the use of prenatal testing results challenging for medical professionals and families.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like BFNE) have only transient symptoms, usually do not interfere with neurocognitive development, and have some treatment available are not common. 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. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

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.

No specific resources for KCNQ2-Related Disorders have been identified by GeneReviews staff.

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

Locus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
EBN1KCNQ220q13​.33Potassium voltage-gated channel subfamily KQT member 2KCNQ2 databaseKCNQ2

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

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

121200SEIZURES, BENIGN FAMILIAL NEONATAL, 1; BFNS1
602235POTASSIUM CHANNEL, VOLTAGE-GATED, KQT-LIKE SUBFAMILY, MEMBER 2; KCNQ2
613720EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 7; EIEE7

Molecular Genetic Pathogenesis

KCNQ2 encodes for potassium channel subunits that are mainly (though not exclusively) expressed in the nervous system. KCNQ2 subunits form heteromultimeric channels with homologous subunits encoded by KCNQ3. Heterotetrameric channels formed by KCNQ2 and KCNQ3 subunits mediate the so-called M-current (IKM), a slowly activating, non-inactivating potassium conductance that inhibits neuronal excitability. Suppression of IKM upon activation of G-protein-coupled receptors (including muscarinic receptors, hence the term M-current) increases neuronal excitability.

Studies on the functional consequences of BFNE-causing KCNQ2 mutations in heterologous expression systems 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, an altered regulation of their function by associated proteins (e.g., calmodulin, Ankirin-G), and a reduced sensitivity to changes in membrane potential by correctly assembled channels [Dedek et al 2001, Castaldo et al 2002].

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 3251 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 that lacks two in-frame exons, resulting in a protein product without Lys417-Ser446 and the single residue Glu509.

Transcript variant 5 (NM_172109.1) is the shortest one, and it 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 Symbol.

Benign allelic variants. Two validated missense benign variants in exon 17 are also described for KCNQ2 isoform a (see Table 3).

Pathogenic allelic variants.The first mutations in KCNQ2-related disorders were described in 1998 [Biervert et al 1998, Singh et al 1998].

Table 2 (pdf) lists the mutations in KCNQ2 responsible for KCNQ2-related disorders currently available in the literature. Note: In this table, for clarity and homogeneity among different isoform sequences used throughout the literature, the ATG translation start codon is given nucleotide position 1.

Collectively, these data suggest that KCNQ2 is the main locus for BFNE, being affected in more than 90% of the cases in which mutations are found. Missense, nonsense, and frameshift mutations leading to truncated or extended protein sequences have been described, with most families showing a “private” genetic alteration; while most missense mutations alter the sequence of the transmembrane region of the protein, the largest number of mutations fall within the long C-terminus domain.

In two BFNE cases in which multiple exonic 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 courses of individuals with deletions of both KCNQ2 and CHRNA4 were those of typical BFNE, and none presented with the phenotype of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), another focal epilepsy caused by mutations in CHRNA4.

Table 3. KCNQ2 Allelic Variants Discussed in This GeneReview

Class of Variant AlleleDNA Nucleotide Change Protein Amino Acid Change Reference Sequences
Benignc. 2516A>Cp.Asn780ThrNM_172107​.2
NP_742105​.1
c. 2741C>Tp.Ser855Leu
Pathogenic 1c.619C>T 2p.Arg207Trp
c.620G>A 2p.Arg207Gln
c.967C>Tp.Gln323Ter
c.2127delTp.Val710SerfsTer220
Multiexonic deletion--
Contiguous gene deletion--

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

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1 See also Table 2.

2. Associated with myokymia (see Genetically Related Disorders and Natural History)

Normal gene product. The KCNQ gene family consists of five members (KCNQ1-5), all encoding voltage-gated potassium channel subunits, each showing distinct tissue distribution and subcellular localization, as well as biophysical, pharmacologic, and pathophysiologic properties [Miceli et al 2008, Soldovieri et al 2011]. KCNQ1 subunits are mainly expressed in cardiac muscle, gastrointestinal epithelia, and inner ear. In the heart, they form the molecular basis of IKs, a cardiac current involved in action potential repolarization [Sanguinetti et al 1996]; in humans, mutations in KCNQ1 are responsible for one form of long QT syndrome (LQTS-1) [Wang et al 1996]. KCNQ2-5 genes were first found to be expressed in neurons; thus, they are currently identified as neural KCNQ genes [Brown & Passmore 2009]. While KCNQ2 and KCNQ3 are expressed in the central and peripheral nervous system, KCNQ4 appears to be mainly expressed in the cochlea and central auditory pathways; mutations targeting KCNQ4 cause a rare form of nonsyndromic autosomal dominant hearing loss (DFNA2) [Kubisch et al 1999]. KCNQ5 transcripts have been detected in several brain regions and in sympathetic ganglia [Lerche et al 2000, Schroeder et al 2000]. More recently, transcripts and subunits encoded by several KCNQ genes have been also detected in smooth muscle [Yeung et al 2007, Mackie et al 2008] and skeletal muscle [Iannotti et al 2010].

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 (IKM) [Brown & Adams 1980, Wang et al 1998], showing a critical role in spike-frequency adaptation and neuronal excitability control.

KCNQ2 subunits, similarly to other voltage-gated potassium channel subunits, encompass six transmembrane domains, with cytoplasmic N-terminal (short) and C-terminal (longer) regions.

Abnormal gene product. Table 2 lists information currently available on mutations causing KCNQ2-related disorders. Whenever possible, a short comment on the functional consequences of the abnormal gene product has also been added.

References

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Chapter Notes

Acknowledgments

The Authors acknowledge funding agencies for supporting their studies; in particular: Telethon GP07125, E-Rare JTC 2007 (EUROBFNS), and PRIN 2009. The collaboration of patients and their families is also highly appreciated.

Author History

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

Revision History

  • 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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